Novel substituted pyrido-piperazinone derivatives as gamma secretase modulators

ABSTRACT

The present invention is concerned with novel substituted pyrido-piperazinone derivatives of Formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , R 5 , L, Z and X have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

FIELD OF THE INVENTION

The present invention is concerned with novel substitutedpyrido-piperazinone derivatives useful as gamma secretase modulators.The invention further relates to processes for preparing such novelcompounds, pharmaceutical compositions comprising said compounds as anactive ingredient as well as the use of said compounds as a medicament.

BACKGROUND OF THE INVENTION

Alzheimer's Disease (AD) is a progressive neurodegenerative disordermarked by loss of memory, cognition, and behavioral stability. ADafflicts 6-10% of the population over age 65 and up to 50% over age 85.It is the leading cause of dementia and the third leading cause of deathafter cardiovascular disease and cancer. There is currently no effectivetreatment for AD. The total net cost related to AD in the U.S. exceeds$100 billion annually.

AD does not have a simple etiology, however, it has been associated withcertain risk factors including (1) age, (2) family history and (3) headtrauma; other factors include environmental toxins and low levels ofeducation. Specific neuropathological lesions in the limbic and cerebralcortices include intracellular neurofibrillary tangles consisting ofhyperphosphorylated tau protein and the extracellular deposition offibrillar aggregates of amyloid beta peptides (amyloid plaques). Themajor components of amyloid plaques are the amyloid beta (A-beta, Abetaor Aβ) peptides of various lengths. A variant thereof, which is theAβ1-42-peptide (Abeta-42), is believed to be the major causative agentfor amyloid formation. Another variant is the Aβ1-40-peptide (Abeta-40).Aβ is the proteolytic product of a precursor protein, beta amyloidprecursor protein (beta-APP or APP).

Familial, early onset autosomal dominant forms of AD have been linked tomissense mutations in the β-amyloid precursor protein (β-APP or APP) andin the presenilin proteins 1 and 2. In some patients, late onset formsof AD have been correlated with a specific allele of the apolipoproteinE (ApoE) gene, and, more recently, the finding of a mutation inalpha2-macroglobulin, which may be linked to at least 30% of the ADpopulation. Despite this heterogeneity, all forms of AD exhibit similarpathological findings. Genetic analysis has provided the best clues fora logical therapeutic approach to AD. All mutations found to date,affect the quantitative or qualitative production of the amyloidogenicpeptides known as Abeta-peptides (Aβ), specifically Aβ42, and have givenstrong support to the “amyloid cascade hypothesis” of AD (Tanzi andBertram, 2005, Cell 120, 545). The likely link between Aβ peptidegeneration and AD pathology emphasizes the need for a betterunderstanding of the mechanisms of Aβ production and strongly warrants atherapeutic approach at modulating Aβ levels.

The release of Aβ peptides is modulated by at least two proteolyticactivities referred to as β- and γ-secretase cleavage at the N-terminus(Met-Asp bond) and the C-terminus (residues 37-42) of the Aβ peptide,respectively. In the secretory pathway, there is evidence thatβ-secretase cleaves first, leading to the secretion of s-APPβ (sβ) andthe retention of a 11 kDa membrane-bound carboxy terminal fragment(CTF). The latter is believed to give rise to Aβ peptides followingcleavage by γ-secretase. The amount of the longer isoform, Aβ42, isselectively increased in patients carrying certain mutations in theregion of a particular gene coding in a particular protein (presenilin),and these mutations have been correlated with early-onset familial AD.Therefore, Aβ42 is believed by many researchers to be the main culpritof the pathogenesis of AD.

It has now become clear that the γ-secretase activity cannot be ascribedto a single protein, but is in fact associated with an assembly ofdifferent proteins.

The gamma (γ)-secretase activity resides within a multiprotein complexcontaining at least four components: the presenilin (PS) heterodimer,nicastrin, aph-1 and pen-2. The PS heterodimer consists of the amino-and carboxyterminal PS fragments generated by endoproteolysis of theprecursor protein. The two aspartates of the catalytic site are at theinterface of this heterodimer. It has recently been suggested thatnicastrin serves as a gamma-secretase-substrate receptor. The functionsof the other members of gamma-secretase are unknown, but they are allrequired for activity (Steiner, 2004. Curr. Alzheimer Research 1(3):175-181).

Thus, although the molecular mechanism of the second cleavage-step hasremained elusive until now, the γ-secretase-complex has become one ofthe prime targets in the search for compounds for the treatment of AD.

Various strategies have been proposed for targeting γ-secretase in AD,ranging from targeting the catalytic site directly, developingsubstrate-specific inhibitors and modulators of γ-secretase activity(Marjaux et al., 2004. Drug Discovery Today: Therapeutic Strategies,Volume 1, 1-6). Accordingly, a variety of compounds were described thathave secretases as targets (Lamer, 2004. Secretases as therapeuticstargets in AD: patents 2000-2004. Expert Opin. Ther. Patents 14,1403-1420).

Indeed, this finding was supported by biochemical studies in which aneffect of certain Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) onγ-secretase was shown (US 2002/0128319; Eriksen (2003) J. Clin. Invest.112, 440). Potential limitations for the use of NSAIDs to prevent ortreat AD are their inhibition activity of cyclooxygenase (COX) enzymes,which can lead to unwanted side effects, and their low CNS penetration(Peretto et al., 2005, J. Med. Chem. 48, 5705-5720). More recently theNSAID R-flurbiprofen, an enantiomer lacking Cox-inhibitory activity andrelated gastric toxicity, has failed in large phase III trial since thedrug did not improve thinking ability or the ability of patients tocarry out daily activities significantly more than those patients onplacebo.

WO-2010/100606 discloses phenyl imidazoles and phenyl triazoles for useas gamma-secretase modulators.

US20090062529 relates to polycyclic compounds effective as therapeuticor prophylactic agents for a disease caused by Aβ.

WO-2010/070008 is concerned with novel substituted bicyclic imidazolederivatives useful as γ-secretase modulators.

WO-2010/089292 is concerned with novel substituted bicyclic heterocycliccompounds useful as γ-secretase modulators.

WO-2011/006903 is concerned with novel substituted triazole andimidazole derivatives useful as γ-secretase modulators.

WO-2012/131539 relates to novel bicyclic pyridinones useful asbrain-penetrable γ-secretase modulators.

There is a strong need for novel compounds which modulate γ-secretaseactivity thereby opening new avenues for the treatment of AD. It is anobject of the present invention to overcome or ameliorate at least oneof the disadvantages of the prior art, or to provide a usefulalternative. The compounds of the present invention or part of thecompounds of the present invention may have improved metabolic stabilityproperties, improved central brain availability, improved solubilities,or reduced CYP inhibition compared with the compounds disclosed in theprior art. It is accordingly an object of the present invention toprovide such novel compounds.

SUMMARY OF THE INVENTION

It has been found that the compounds of the present invention are usefulas γ-secretase modulators. The compounds according to the invention andthe pharmaceutically acceptable compositions thereof, may be useful inthe treatment or prevention of AD.

The present invention concerns novel compounds of Formula (I):

-   tautomers and stereoisomeric forms thereof, wherein-   R¹ is Ar¹ or Ar²;-   R² is hydrogen, phenyl, cycloC₃₋₇alkyl, 3,4,5,6-tetrahydropyranyl,    3,4,5,6-tetrahydrothiopyranyl, piperidinyl, or C₁₋₄alkyl optionally    substituted with one or more substituents each independently    selected from the group consisting of halo, hydroxyl, C₁₋₄alkyloxy    and NR⁷R⁸;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is a covalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,    -   C₁₋₆alkanediyl optionally substituted with one or more        substituents selected from the group consisting of        3,4,5,6-tetrahydropyranyl, phenyl and C₁₋₄alkyloxy-C₁₋₄alkyl, or    -   C₁₋₆alkanediyl wherein two geminal hydrogen atoms are replaced        by C₂₋₆alkanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl,    isoxazolyl, isothiazolyl, thienyl, thiazolyl, pyrrolidinyl,    piperidinyl, pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl,    1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl,    1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,    1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,    3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and    1,2,3,4-tetrahydroquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, oxo, Ar³, R⁰, C₁₋₄alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁₋₄alkyloxy and        cycloC₃₋₇alkyl, and C₁₋₄alkyloxy optionally substituted with one        or more substituents each independently selected from the group        consisting of halo and cycloC₃₋₇alkyl;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of halo,    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and    -   C₁₋₄alkyl optionally substituted with one or more halo        substituents;-   Ar³ is phenyl optionally substituted with one or more substituents    each independently selected from the group consisting of halo and    C₁₋₄alkyl optionally substituted with one or more halo substituents;-   R³ is hydrogen, cyano, halo, C₁₋₄alkyloxy or C₁₋₄alkyl;-   R⁴ is hydrogen, halo or C₁₋₄alkyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   X is CR⁶ or N;-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁷ is hydrogen or C₁₋₄alkyl;-   R⁸ is hydrogen or C₁₋₄alkyl;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   R⁰ is a ring system selected from the group consisting of    piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl and    pyrrolidinyl; wherein said ring system is optionally substituted    with one or more substituents each independently selected from the    group consisting of halo or C₁₋₄alkyl optionally substituted with    one or more halo atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

The present invention also concerns methods for the preparation ofcompounds of the present invention and pharmaceutical compositionscomprising them.

The compounds of the present invention were found to modulate theγ-secretase activity in vitro and in vivo, and therefore may be usefulin the treatment or prevention of AD, traumatic brain injury (TBI),dementia pugilistica, mild cognitive impairment (MCI), senility,dementia, dementia with Lewy bodies, cerebral amyloid angiopathy,multi-infarct dementia, Down's syndrome, dementia associated withParkinson's disease and dementia associated with beta-amyloid;preferably AD and other disorders with Beta-amyloid pathology (e.g.glaucoma).

In view of the aforementioned pharmacology of the compounds of Formula(I) and the pharmaceutically acceptable addition salts, and the solvatesthereof, it follows that they may be suitable for use as a medicament.

More especially the compounds of Formula (I) and the pharmaceuticallyacceptable addition salts, and the solvates thereof, may be suitable inthe treatment or prevention of AD, cerebral amyloid angiopathy,multi-infarct dementia, dementia pugilistica and Down syndrome.

The present invention also concerns the use of compounds according tothe general Formula (I), and the pharmaceutically acceptable acid orbase addition salts and the solvates thereof, for the manufacture of amedicament for the modulation of γ-secretase activity.

The present invention will now be further described. In the followingpassages, different aspects of the invention are defined in more detail.Each aspect so defined may be combined with any other aspect or aspectsunless clearly indicated to the contrary. In particular, any featureindicated as being preferred or advantageous may be combined with anyother feature or features indicated as being preferred or advantageous.

DETAILED DESCRIPTION

When describing the compounds of the invention, the terms used are to beconstrued in accordance with the following definitions, unless a contextdictates otherwise.

Whenever the term “substituted” is used in the present invention, it ismeant, unless otherwise is indicated or is clear from the context, toindicate that one or more hydrogens, in particular from 1 to 3hydrogens, preferably 1 or 2 hydrogens, more preferably 1 hydrogen, onthe atom or radical indicated in the expression using “substituted” arereplaced with a selection from the indicated group, provided that thenormal valency is not exceeded, and that the substitution results in achemically stable compound, i.e. a compound that is sufficiently robustto survive isolation to a useful degree of purity from a reactionmixture, and formulation into a therapeutic agent.

The term “halo” as a group or part of a group is generic for fluoro,chloro, bromo, iodo unless otherwise is indicated or is clear from thecontext.

The term “C₁₋₄alkyl” as a group or part of a group refers to ahydrocarbyl radical of Formula C_(n)H_(2n+1) wherein n is a numberranging from 1 to 4. C₁₋₄alkyl groups comprise from 1 to 4 carbon atoms,preferably from 1 to 3 carbon atoms, more preferably 1 to 2 carbonatoms. C₁₋₄alkyl groups may be linear or branched and may be substitutedas indicated herein. When a subscript is used herein following a carbonatom, the subscript refers to the number of carbon atoms that the namedgroup may contain. C₁₋₄alkyl includes all linear, or branched alkylgroups with between 1 and 4 carbon atoms, and thus includes such as forexample methyl, ethyl, n-propyl, i-propyl, 2-methyl-ethyl, butyl and itsisomers (e.g. n-butyl, isobutyl and tert-butyl), and the like.

The term “cycloC₃₋₇alkyl” alone or in combination, refers to a cyclicsaturated hydrocarbon radical having from 3 to 7 carbon atoms.Non-limiting examples of suitable cycloC₃₋₇alkyl include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term “C₁₋₄alkyloxy” as a group or part of a group refers to aradical having the Formula OR^(b) wherein R^(b) is C₁₋₄alkyl.Non-limiting examples of suitable C₁₋₄alkyloxy include methyloxy (alsomethoxy), ethyloxy (also ethoxy), propyloxy, isopropyloxy, butyloxy,isobutyloxy, sec-butyloxy and tert-butyloxy.

The term “C₁₋₆alkanediyl” as a group or part of a group defines bivalentstraight or branched chained saturated hydrocarbon radicals having from1 to 6 carbon atoms such as, for example, methylene or methanediyl,ethan-1,2-diyl, ethan-1,1-diyl or ethylidene, propan-1,3-diyl,propan-1,2-diyl, butan-1,4-diyl, pentan-1,5-diyl, pentan-1,1-diyl,hexan-1,6-diyl, 2-methylbutan-1,4-diyl, 3-methylpentan-1,5-diyl and thelike.

The term “C₂₋₆alkanediyl” as a group or part of a group defines bivalentstraight or branched chained saturated hydrocarbon radicals having from2 to 6 carbon atoms such as, for example, ethan-1,2-diyl, ethan-1,1-diylor ethylidene, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl,pentan-1,5-diyl, pentan-1,1-diyl, hexan-1,6-diyl,2-methylbutan-1,4-diyl, 3-methylpentan-1,5-diyl and the like;

in particular “C₂₋₆alkanediyl” as a group or part of a group definesethan-1,2-diyl.

Similarly, the term “C₁₋₂alkanediyl” as a group or part of a groupdefines bivalent straight or branched chained saturated hydrocarbonradicals having from 1 to 2 carbon atoms.

The term “oxo” means ═O.

The term “3,4-dihydro-1-benzopyranyl” is equivalent to3,4-dihydro-2H-1-benzopyranyl, “indazolyl” is equivalent to1H-indazolyl, “3,4-dihydro-2-benzothiopyranyl” is equivalent to3,4-dihydro-1H-2-benzothiopyranyl, “3,4-dihydro-2-benzopyranyl” isequivalent to 3,4-dihydro-1H-2-benzopyranyl, “3,4,5,6-tetrahydropyranyl”is equivalent to tetrahydro-2H-pyranyl, “3,4,5,6-tetrahydrothiopyranyl”is equivalent to tetrahydro-2H-thiopyranyl.

Whenever variable ‘L’ represents —C(═O)—C₁₋₆alkanediyl-, it is intendedthat the carbonyl group is attached to ‘R¹’ and C₁₋₆alkanediyl isattached to the remainder of the molecule. This is illustrated byformula (I′):

The chemical names of the compounds of the present invention weregenerated according to the nomenclature rules agreed upon by theChemical Abstracts Service, using Advanced Chemical Development, Inc.,nomenclature software (ACD/Labs Release 12.00 Product version 12.01;Build 33104, 27 May 2009). In case of tautomeric forms, the name of thedepicted tautomeric form was generated. It should be clear that theother non-depicted tautomeric form is also included within the scope ofthe present invention.

Whenever one of the ring systems in the definition of Ar¹ or R⁰ issubstituted with one or more substituents, those substituents mayreplace any hydrogen atom bound to a carbon or nitrogen atom of the ringsystem.

The term “compounds of the invention” as used herein, is meant toinclude the compounds of Formula (I), and the salts and solvatesthereof.

As used herein, any chemical formula with bonds shown only as solidlines and not as solid wedged or hashed wedged bonds, or otherwiseindicated as having a particular configuration (e.g. R, S) around one ormore atoms, contemplates each possible stereoisomer, or mixture of twoor more stereoisomers.

Hereinbefore and hereinafter, the term “compound of Formula (I)” ismeant to include the stereoisomers thereof and the tautomeric formsthereof.

The terms “stereoisomers”, “stereoisomeric forms” or “stereochemicallyisomeric forms” hereinbefore or hereinafter are used interchangeably.

The invention includes all stereoisomers of the compounds of theinvention either as a pure stereoisomer or as a mixture of two or morestereoisomers.

Enantiomers are stereoisomers that are non-superimposable mirror imagesof each other. A 1:1 mixture of a pair of enantiomers is a racemate orracemic mixture.

Diastereomers (or diastereoisomers) are stereoisomers that are notenantiomers, i.e. they are not related as mirror images. If a compoundcontains a double bond, the substituents may be in the E or the Zconfiguration. Substituents on bivalent cyclic (partially) saturatedradicals may have either the cis- or trans-configuration; for example ifa compound contains a disubstituted cycloalkyl group, the substituentsmay be in the cis or trans configuration. Therefore, the inventionincludes enantiomers, diastereomers, racemates, E isomers, Z isomers,cis isomers, trans isomers and mixtures thereof, whenever chemicallypossible.

The meaning of all those terms, i.e. enantiomers, diastereomers,racemates, E isomers, Z isomers, cis isomers, trans isomers and mixturesthereof are known to the skilled person.

The absolute configuration is specified according to theCahn-Ingold-Prelog system. The configuration at an asymmetric atom isspecified by either R or S. Resolved stereoisomers whose absoluteconfiguration is not known can be designated by (+) or (−) depending onthe direction in which they rotate plane polarized light. For instance,resolved enantiomers whose absolute configuration is not known can bedesignated by (+) or (−) depending on the direction in which they rotateplane polarized light.

When a specific stereoisomer is identified, this means that saidstereoisomer is substantially free, i.e. associated with less than 50%,preferably less than 20%, more preferably less than 10%, even morepreferably less than 5%, in particular less than 2% and most preferablyless than 1%, of the other stereoisomers. Thus, when a compound ofFormula (I) is for instance specified as (R), this means that thecompound is substantially free of the (S) isomer; when a compound ofFormula (I) is for instance specified as E, this means that the compoundis substantially free of the Z isomer; when a compound of Formula (I) isfor instance specified as cis, this means that the compound issubstantially free of the trans isomer.

Some of the compounds according to Formula (I) may also exist in theirtautomeric form. Such forms in so far as they may exist, although notexplicitly indicated in the above Formula (I) are intended to beincluded within the scope of the present invention.

It follows that a single compound may exist in both stereoisomeric andtautomeric form.

For therapeutic use, salts of the compounds of Formula (I) and solvatesthereof, are those wherein the counterion is pharmaceuticallyacceptable. However, salts of acids and bases which arenon-pharmaceutically acceptable may also find use, for example, in thepreparation or purification of a pharmaceutically acceptable compound.All salts, whether pharmaceutically acceptable or not are includedwithin the ambit of the present invention.

The pharmaceutically acceptable acid and base addition salts asmentioned hereinabove or hereinafter are meant to comprise thetherapeutically active non-toxic acid and base addition salt forms whichthe compounds of Formula (I) and solvates thereof, are able to form. Thepharmaceutically acceptable acid addition salts can conveniently beobtained by treating the base form with such appropriate acid.Appropriate acids comprise, for example, inorganic acids such ashydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric,nitric, phosphoric and the like acids; or organic acids such as, forexample, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids. Conversely said salt formscan be converted by treatment with an appropriate base into the freebase form.

The compounds of Formula (I) and solvates thereof containing an acidicproton may also be converted into their non-toxic metal or amineaddition salt forms by treatment with appropriate organic and inorganicbases. Appropriate base salt forms comprise, for example, the ammoniumsalts, the alkali and earth alkaline metal salts, e.g. the lithium,sodium, potassium, magnesium, calcium salts and the like, salts withorganic bases, e.g. primary, secondary and tertiary aliphatic andaromatic amines such as methylamine, ethylamine, propylamine,isopropylamine, the four butylamine isomers, dimethylamine,diethylamine, diethanolamine, dipropylamine, diisopropylamine,di-n-butylamine, pyrrolidine, piperidine, morpholine, trimethylamine,triethylamine, tripropylamine, quinuclidine, pyridine, quinoline andisoquinoline; the benzathine, N-methyl-D-glucamine, hydrabamine salts,and salts with amino acids such as, for example, arginine, lysine andthe like. Conversely the salt form can be converted by treatment withacid into the free acid form.

The term solvate comprises the hydrates and solvent addition forms whichthe compounds of Formula (I) are able to form, as well as thepharmaceutically acceptable salts thereof. Examples of such forms aree.g. hydrates, alcoholates and the like.

The compounds of the invention as prepared in the processes describedbelow may be synthesized in the form of mixtures of enantiomers, inparticular racemic mixtures of enantiomers, that can be separated fromone another following art-known resolution procedures. An manner ofseparating the enantiomeric forms of the compounds of Formula (I) andthe pharmaceutically acceptable addition salts, and the solvatesthereof, involves liquid chromatography using a chiral stationary phase.Said pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically. Preferably if a specific stereoisomer is desired,said compound would be synthesized by stereospecific methods ofpreparation. These methods will advantageously employ enantiomericallypure starting materials.

In the framework of this application, an element, in particular whenmentioned in relation to a compound according to Formula (I), comprisesall isotopes and isotopic mixtures of this element, either naturallyoccurring or synthetically produced, either with natural abundance or inan isotopically enriched form. Radiolabelled compounds of Formula (I)may comprise a radioactive isotope selected from the group of ³H, ¹¹C,¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and ⁸²Br. Preferably, theradioactive isotope is selected from the group of ³H, ¹¹C and ¹⁸F.

As used in the specification and the appended claims, the singular forms“a”, “an,” and “the” also include plural referents unless the contextclearly dictates otherwise. For example, “a compound” means 1 compoundor more than 1 compound.

In an embodiment, the present invention concerns novel compounds ofFormula (I):

-   tautomers and stereoisomeric forms thereof, wherein-   R¹ is Ar¹ or Ar²;-   R² is hydrogen, phenyl, cycloC₃₋₇alkyl, 3,4,5,6-tetrahydropyranyl,    3,4,5,6-tetrahydrothiopyranyl, piperidinyl, or C₁₋₄alkyl optionally    substituted with one or more substituents each independently    selected from the group consisting of halo, hydroxyl, C₁₋₄alkyloxy    and NR⁷R⁸;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is a covalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,    -   C₁₋₆alkanediyl optionally substituted with one or more        substituents selected from the group consisting of        3,4,5,6-tetrahydropyranyl, phenyl and C₁₋₄alkyloxy-C₁₋₄alkyl, or    -   C₁₋₆alkanediyl wherein two geminal hydrogen atoms are replaced        by C₂₋₆alkanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl,    isoxazolyl, isothiazolyl, thienyl, thiazolyl, pyrrolidinyl,    piperidinyl, pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl,    1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl,    1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,    1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,    3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and    1,2,3,4-tetrahydroquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, oxo, Ar³, R⁰, C₁₋₄alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁₋₄alkyloxy and        cycloC₃₋₇alkyl, and C₁₋₄alkyloxy optionally substituted with one        or more substituents each independently selected from the group        consisting of halo and cycloC₃₋₇alkyl;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of halo,    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and    -   C₁₋₄alkyl optionally substituted with one or more halo        substituents;-   Ar³ is phenyl optionally substituted with one or more substituents    each independently selected from the group consisting of halo and    C₁₋₄alkyl optionally substituted with one or more halo substituents;-   R³ is hydrogen, cyano, halo, C₁₋₄alkyloxy or C₁₋₄alkyl;-   R⁴ is hydrogen, halo or C₁₋₄alkyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   X is CR⁶ or N;-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁷ is hydrogen or C₁₋₄alkyl;-   R⁸ is hydrogen or C₁₋₄alkyl;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   R⁰ is a ring system selected from the group consisting of    piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl and    pyrrolidinyl; wherein said ring system is optionally substituted    with one or more substituents each independently selected from the    group consisting of halo or C₁₋₄alkyl optionally substituted with    one or more halo atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar¹;-   R² is hydrogen, phenyl, cycloC₃₋₇alkyl, 3,4,5,6-tetrahydropyranyl,    3,4,5,6-tetrahydrothiopyranyl, piperidinyl, or C₁₋₄alkyl optionally    substituted with one or more substituents each independently    selected from the group consisting of halo, hydroxyl, C₁₋₄alkyloxy    and NR⁷R⁸;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is a covalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,    -   C₁₋₆alkanediyl optionally substituted with one or more        substituents selected from the group consisting of        3,4,5,6-tetrahydropyranyl, phenyl and C₁₋₄alkyloxy-C₁₋₄alkyl, or    -   C₁₋₆alkanediyl wherein two geminal hydrogen atoms are replaced        by C₂₋₆alkanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl,    isoxazolyl, isothiazolyl, thienyl, thiazolyl, pyrrolidinyl,    piperidinyl, pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl,    1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl,    1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,    1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,    3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and    1,2,3,4-tetrahydroquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, oxo, Ar^(a), R⁰, C₁₋₄alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁₋₄alkyloxy and        cycloC₃₋₇alkyl, and C₁₋₄alkyloxy optionally substituted with one        or more substituents each independently selected from the group        consisting of halo and cycloC₃₋₇alkyl;-   Ar³ is phenyl optionally substituted with one or more substituents    each independently selected from the group consisting of halo and    C₁₋₄alkyl optionally substituted with one or more halo substituents;-   R³ is hydrogen, cyano, halo, C₁₋₄alkyloxy or C₁₋₄alkyl;-   R⁴ is hydrogen, halo or C₁₋₄alkyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   X is CR⁶ or N;-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁷ is hydrogen or C₁₋₄alkyl;-   R⁸ is hydrogen or C₁₋₄alkyl;-   R⁰ is a ring system selected from the group consisting of    piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl and    pyrrolidinyl; wherein said ring system is optionally substituted    with one or more substituents each independently selected from the    group consisting of halo or C₁₋₄alkyl optionally substituted with    one or more halo atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar²;-   R² is hydrogen, phenyl, cycloC₃₋₇alkyl, 3,4,5,6-tetrahydropyranyl,    3,4,5,6-tetrahydrothiopyranyl, piperidinyl, or C₁₋₄alkyl optionally    substituted with one or more substituents each independently    selected from the group consisting of halo, hydroxyl, C₁₋₄alkyloxy    and NR⁷R⁸;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is a covalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,    -   C₁₋₆alkanediyl optionally substituted with one or more        substituents selected from the group consisting of        3,4,5,6-tetrahydropyranyl, phenyl and C₁₋₄alkyloxy-C₁₋₄alkyl, or    -   C₁₋₆alkanediyl wherein two geminal hydrogen atoms are replaced        by C₂₋₆alkanediyl;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of halo,    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and    -   C₁₋₄alkyl optionally substituted with one or more halo        substituents;-   R³ is hydrogen, cyano, halo, C₁₋₄alkyloxy or C₁₋₄alkyl;-   R⁴ is hydrogen, halo or C₁₋₄alkyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   X is CR⁶ or N;-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁷ is hydrogen or C₁₋₄alkyl;-   R⁸ is hydrogen or C₁₋₄alkyl;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar¹ or Ar²;-   R² is methyl;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is a covalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,    -   C₁₋₆alkanediyl optionally substituted with one or more        substituents selected from the group consisting of        3,4,5,6-tetrahydropyranyl, phenyl and C₁₋₄alkyloxy-C₁₋₄alkyl, or    -   C₁₋₆alkanediyl wherein two geminal hydrogen atoms are replaced        by C₂₋₆alkanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl,    isoxazolyl, isothiazolyl, thienyl, thiazolyl, pyrrolidinyl,    piperidinyl, pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl,    1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl,    1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,    1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,    3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and    1,2,3,4-tetrahydroquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, oxo, Ar^(a), R⁰, C₁₋₄ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁₋₄alkyloxy and        cycloC₃₋₇alkyl, and C₁₋₄alkyloxy optionally substituted with one        or more substituents each independently selected from the group        consisting of halo and cycloC₃₋₇alkyl;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of halo,    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and    -   C₁₋₄alkyl optionally substituted with one or more halo        substituents;-   Ar³ is phenyl optionally substituted with one or more substituents    each independently selected from the group consisting of halo and    C₁₋₄alkyl optionally substituted with one or more halo substituents;-   R³ is hydrogen, cyano, halo, C₁₋₄alkyloxy or C₁₋₄alkyl;-   R⁴ is hydrogen, halo or C₁₋₄alkyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   X is CR⁶ or N;-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁷ is hydrogen or C₁₋₄alkyl;-   R⁸ is hydrogen or C₁₋₄alkyl;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   R⁰ is a ring system selected from the group consisting of    piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl and    pyrrolidinyl; wherein said ring system is optionally substituted    with one or more substituents each independently selected from the    group consisting of halo or C₁₋₄alkyl optionally substituted with    one or more halo atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar¹ or Ar²;-   R² is hydrogen or C₁₋₄alkyl;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is a covalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,    C₁₋₆alkanediyl or C₁₋₆alkanediyl wherein two geminal hydrogen atoms    are replaced by C₂₋₆alkanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl,    isoxazolyl, isothiazolyl, thienyl, thiazolyl, pyrrolidinyl,    piperidinyl, pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl,    1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl,    1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,    1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,    3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and    1,2,3,4-tetrahydroquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, oxo, C₁₋₄alkyl optionally substituted with        one or more substituents each independently selected from the        group consisting of halo, C₁₋₄alkyloxy and cycloC₃₋₇alkyl, and        C₁₋₄alkyloxy optionally substituted with one or more        substituents each independently selected from the group        consisting of halo and cycloC₃₋₇alkyl;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of halo,    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and    -   C₁₋₄alkyl optionally substituted with one or more halo        substituents;-   R³ is hydrogen; R⁴ is C₁₋₄alkyl; R⁵ is hydrogen; X is CR⁶; R⁶ is    hydrogen;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   R⁰ is piperidinyl optionally substituted with one or more    substituents each independently selected from the group consisting    of halo or C₁₋₄alkyl optionally substituted with one or more halo    atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar¹ or Ar²;-   R² is methyl;-   Z is methylene or 1,2-ethanediyl, wherein methylene or    1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkyl    substituents;-   L is C₁₋₆alkanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl,    isoxazolyl, isothiazolyl, thienyl, thiazolyl, pyrrolidinyl,    piperidinyl, pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl,    1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl,    1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,    1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,    3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and    1,2,3,4-tetrahydroquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, oxo, Ar³, R⁰, C₁₋₄alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of halo, C₁₋₄alkyloxy and        cycloC₃₋₇alkyl, and C₁₋₄alkyloxy optionally substituted with one        or more substituents each independently selected from the group        consisting of halo and cycloC₃₋₇alkyl;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of halo,    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and    -   C₁₋₄alkyl optionally substituted with one or more halo        substituents;-   Ar³ is phenyl optionally substituted with one or more substituents    each independently selected from the group consisting of halo and    C₁₋₄alkyl optionally substituted with one or more halo substituents;-   R³ is hydrogen, cyano, halo, C₁₋₄alkyloxy or C₁₋₄alkyl;-   R⁴ is hydrogen, halo or C₁₋₄alkyl;-   R⁵ is hydrogen or C₁₋₄alkyl;-   X is CR⁶ or N;-   R⁶ is hydrogen or C₁₋₄alkyl;-   R⁷ is hydrogen or C₁₋₄alkyl;-   R⁸ is hydrogen or C₁₋₄alkyl;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   R⁰ is a ring system selected from the group consisting of    piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl and    pyrrolidinyl; wherein said ring system is optionally substituted    with one or more substituents each independently selected from the    group consisting of halo or C₁₋₄alkyl optionally substituted with    one or more halo atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar¹ or Ar²;-   R² is hydrogen or C₁₋₄alkyl;-   Z is methylene;-   L is a covalent bond, —C(═O)—C₁₋₆alkanediyl-, C₁₋₆alkanediyl, or    C₁₋₆alkanediyl wherein two geminal hydrogen atoms are replaced by    C₂₋₆ alkanediyl;-   Ar¹ is a ring system selected from the group consisting of thienyl,    thiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl,    4,5,6,7-tetrahydro-benzo[b]thienyl, 1,2-benzisoxazolyl,    benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,    1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,    3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,    1,2,3,4-tetrahydro-isoquinolinyl;    -   wherein said ring system is optionally substituted with one or        more substituents each independently selected from the group        consisting of halo, Ar³, oxo, R⁰, C₁₋₄alkyl optionally        substituted with one or more halo substituents, and        C₁₋₄alkyloxy;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one, two or three substituents    each independently selected from the group consisting of    C₁₋₄alkyloxy optionally substituted with one or more halo    substituents, and C₁₋₄alkyl optionally substituted with one or more    halo substituents;-   Ar³ is phenyl optionally substituted with one or more CF₃    substituents;-   R³ is hydrogen;-   R⁴ is C₁₋₄alkyl;-   R⁵ is hydrogen;-   X is CR⁶;-   R⁶ is hydrogen;-   R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl;-   R⁰ is a ring system selected from the group consisting of    piperidinyl optionally substituted with one or more C₁₋₄alkyl groups    optionally substituted with one or more halo atoms;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment, the present invention concerns novel compounds ofFormula (I), tautomers and stereoisomeric forms thereof, wherein:

-   R¹ is Ar¹ or Ar²;-   R² is hydrogen or methyl;-   Z is methylene;-   L is a covalent bond, —C(═O)—CH₂—, C₁₋₂alkanediyl, or    -   C₁₋₂ alkanediyl wherein two geminal hydrogen atoms are replaced        by 1,2-ethanediyl;-   Ar¹ is a ring system selected from the group consisting of    imidazol-1-yl, 2-thienyl, 3-thienyl, 4-thiazolyl, 3-pyrrolidinyl,    1-piperidinyl, pyrazol-3-yl, pyrazol-5-yl,    4,5,6,7-tetrahydro-benzo[b]thien-3-yl,    4,5,6,7-tetrahydro-benzo[b]thien-2-yl, 1,2-benzisoxazol-3-yl,    2-benzofuranyl, 2,3-dihydro-3-benzofuranyl,    2,3-dihydro-7-benzofuranyl,    2,3-dihydro-2-benzofuranyl,1,3-dihydro-1-isobenzofuranyl,    5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3-yl,    4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl,    1,2,4-triazolo[4,3-a]pyridin-3-yl, pyrazolo-[1,5-a]pyridin-3-yl,    3,4-dihydro-1-benzopyran-2-yl, 3,4-dihydro-1-benzopyran-6-yl,    1,2-benzisothiazol-3-yl, indazol-3-yl,    1,2,3,4-tetrahydro-2-isoquinolinyl; wherein said ring system is    optionally substituted with 1, 2 or 3 substituents each    independently selected from the group consisting of Br, Cl, Ar³,    oxo, R⁰, isopropyloxy and C₁₋₄alkyl optionally substituted with 3    fluoro groups;-   Ar² is phenyl substituted with one substituent selected from the    group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said    phenyl is optionally substituted with one substituent each    independently selected from the group consisting of methyl, CF₃ and    methoxy optionally substituted with 3 fluoro substituents;-   Ar³ is phenyl substituted with one CF₃ group;-   R³ is hydrogen;-   R⁴ is methyl;-   R⁵ is hydrogen;-   X is CH;-   R⁹ is hydrogen, cyclopentyl, cyclopropyl or phenyl;-   R⁰ is a ring system selected from the group consisting of    1-piperidinyl substituted with one CF₃ group;-   and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment, the present invention concerns novel compounds ofFormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein one or more of the following restrictionsapply:

-   (a) R² is phenyl, cycloC₃₋₇alkyl, 3,4,5,6-tetrahydropyranyl,    3,4,5,6-tetrahydrothiopyranyl, piperidinyl, or C₁₋₄alkyl optionally    substituted with one or more substituents each independently    selected from the group consisting of hydroxyl, C₁₋₄alkyloxy and    NR⁷R⁸;-   (b) Z is methylene or 1,2-ethanediyl;-   (c) L is C₁₋₆alkanediyl optionally substituted with one or more    substituents selected from the group consisting of    3,4,5,6-tetrahydropyranyl, phenyl and C₁₋₄alkyloxyC₁₋₄alkyl;-   (d) R³ is hydrogen;-   (e) R⁴ is C₁₋₄alkyl;-   (f) R⁵ is hydrogen;-   (g) X is CR⁶;-   (h) R⁶ is hydrogen;-   (i) R⁷ is C₁₋₄alkyl;-   (j) R⁸ is C₁₋₄alkyl;-   (k) R⁰ is piperidinyl optionally substituted with one or more    substituents each independently selected from the group consisting    of halo or C₁₋₄alkyl optionally substituted with one or more halo    atoms.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R¹ is Ar¹.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R¹ is Ar².

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is hydrogen, phenyl, cycloC₃₋₇alkyl,3,4,5,6-tetrahydropyranyl, 3,4,5,6-tetrahydrothiopyranyl, piperidinyl,or C₁₋₄alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, C₁₋₄alkyloxy and NR⁷R⁸.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is hydrogen or C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is hydrogen.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is C₁₋₄alkyl; in particular methyl.

In an embodiment, the present invention relates to those compounds offormula (I), or any subgroup thereof as mentioned in any of the otherembodiments, wherein R² is hydrogen, phenyl, cycloC₃₋₇alkyl, orC₁₋₄alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl,C₁₋₄alkyloxy and NR⁷R⁸.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is phenyl, cycloC₃₋₇alkyl,3,4,5,6-tetrahydropyranyl, 3,4,5,6-tetrahydrothiopyranyl, piperidinyl,or C₁₋₄alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halo, hydroxyl,C₁₋₄alkyloxy and NR⁷R⁸.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is hydrogen or C₁₋₄alkyl optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of hydroxyl, C₁₋₄alkyloxy and NR⁷R⁸ methyl; inparticular hydrogen or C₁₋₄alkyl; more in particular hydrogen or methyl;even more in particular methyl.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is C₁₋₄alkyl optionally substituted withone or more substituents each independently selected from the groupconsisting of halo, hydroxyl, C₁₋₄alkyloxy and NR⁷R⁸.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is phenyl, cycloC₃₋₇alkyl,3,4,5,6-tetrahydropyranyl, 3,4,5,6-tetrahydrothiopyranyl, piperidinyl,or C₁₋₄alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halo, hydroxyl,C₁₋₄alkyloxy and NR⁷R⁸.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R⁰ is a ring system selected from the groupconsisting of piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl andpyrrolidinyl; wherein said ring system is optionally substituted withone or more C₁₋₄alkyl groups optionally substituted with one or morehalo atoms.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R³ is hydrogen or halo; in particularhydrogen.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R⁸ is C₁₋₄alkyl.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Z is methylene or 1,2-ethanediyl, whereinmethylene is optionally substituted with one or two C₁₋₄alkylsubstituents.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein L is C₁₋₆alkanediyl; in particular L ismethylene, ethylidene or 1,2-ethanediyl; more in particular L isethylidene.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein L is methylene.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is methyl and L is ethylidene ormethylene; in particular wherein R² is methyl and L is ethylidene.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R² is C₁₋₄alkyl and L is C₁₋₆alkanediyl.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein R³ is hydrogen; R⁴ is methyl; R⁵ is hydrogen;X is CH.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein L is —C(═O)—C₁₋₆alkanediyl-, C₁₋₆alkanediyloptionally substituted with one or more substituents selected from thegroup consisting of 3,4,5,6-tetrahydropyranyl, phenyl andC₁₋₄alkyloxyC₁₋₄alkyl, or C₁₋₆alkanediyl wherein two geminal hydrogenatoms are replaced by C₂₋₆alkanediyl; in particular L is C₁₋₆alkanediyloptionally substituted with one or more substituents selected from thegroup consisting of 3,4,5,6-tetrahydropyranyl, phenyl andC₁₋₄alkyloxyC₁₋₄alkyl, or C₁₋₆alkanediyl wherein two geminal hydrogenatoms are replaced by C₂₋₆alkanediyl; more in particular L isC₁₋₆alkanediyl optionally substituted with one or more substituentsselected from the group consisting of 3,4,5,6-tetrahydropyranyl, phenyland C₁₋₄alkyloxyC₁₋₄alkyl.

An interesting group of compounds relates to those compounds wherein theposition of R³ is fixed as shown in (I-x)

tautomers and stereoisomeric forms thereof,wherein all the substituents have the same meaning as defined in any ofthe embodiments hereinbefore, and the pharmaceutically acceptableaddition salts and the solvates thereof.

An interesting group of compounds relates to those compounds of formula(I) and the pharmaceutically acceptable addition salts, and the solvatesthereof, or any subgroups thereof, wherein the carbon atom substitutedwith R² has the R configuration.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Ar¹ is a ring system selected from the groupconsisting of imidazolyl, thienyl, thiazolyl, pyrrolidinyl, piperidinyl,pyrazolyl, 4,5,6,7-tetrahydro-benzo[b]thienyl, 1,2-benzisoxazolyl,benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo-[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,1,2,3,4-tetrahydro-isoquinolinyl; it should be understood that any ofthese ring systems may be substituted as defined in any of the otherembodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Ar¹ is a ring system selected from the groupconsisting of imidazol-1-yl, 2-thienyl, 3-thienyl, 4-thiazolyl,3-pyrrolidinyl, 1-piperidinyl, pyrazol-3-yl, pyrazol-5-yl,4,5,6,7-tetrahydro-benzo[b]thien-3-yl,4,5,6,7-tetrahydro-benzo[b]thien-2-yl, 1,2-benzisoxazol-3-yl,2-benzofuranyl, 3-benzofuranyl, 2,3-dihydro-3-benzofuranyl,2,3-dihydro-7-benzofuranyl,2,3-dihydro-2-benzofuranyl,1,3-dihydro-1-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3-yl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl,1,2,4-triazolo[4,3-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-3-yl,3,4-dihydro-1-benzopyran-2-yl, 3,4-dihydro-1-benzopyran-4-yl,3,4-dihydro-1-benzopyran-6-yl, 1,2-benzisothiazol-3-yl, indazol-3-yl,1,2,3,4-tetrahydro-2-isoquinolinyl;

it should be understood that any of these ring systems may besubstituted as defined in any of the other embodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Ar′ is a ring system selected from the groupconsisting of imidazol-1-yl, 2-thienyl, 3-thienyl, 4-thiazolyl,3-pyrrolidinyl, 1-piperidinyl, pyrazol-3-yl, pyrazol-5-yl,4,5,6,7-tetrahydro-benzo[b]thien-3-yl,4,5,6,7-tetrahydro-benzo[b]thien-2-yl, 1,2-benzisoxazol-3-yl,2-benzofuranyl, 2,3-dihydro-3-benzofuranyl, 2,3-dihydro-7-benzofuranyl,2,3-dihydro-2-benzofuranyl, 1,3-dihydro-1-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo-[4,3-a]pyridin-3-yl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl,1,2,4-triazolo-[4,3-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-3-yl,3,4-dihydro-1-benzopyran-2-yl, 3,4-dihydro-1-benzopyran-6-yl,1,2-benzisothiazol-3-yl, indazol-3-yl,1,2,3,4-tetrahydro-2-isoquinolinyl;

it should be understood that any of these ring systems may besubstituted as defined in any of the other embodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Ar¹ is a ring system selected from the groupconsisting of imidazolyl, thienyl, thiazolyl, pyrrolidinyl, piperidinyl,4,5,6,7-tetrahydro-benzo[b]thienyl, benzofuranyl,2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, indazolyl, 1,2,3,4-tetrahydro-isoquinolinyl;it should be understood that any of these ring systems may besubstituted as defined in any of the other embodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Ar¹ is a ring system selected from the groupconsisting of imidazol-1-yl, 2-thienyl, 3-thienyl, 4-thiazolyl,3-pyrrolidinyl, 1-piperidinyl, 4,5,6,7-tetrahydro-benzo[b]thien-3-yl,4,5,6,7-tetrahydro-benzo[b]thien-2-yl, 2-benzofuranyl, 3-benzofuranyl,2,3-dihydro-3-benzofuranyl, 2,3-dihydro-7-benzofuranyl,2,3-dihydro-2-benzofuranyl, 1,3-dihydro-1-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3-yl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-3-yl,1,2,4-triazolo[4,3-a]pyridin-3-yl, pyrazolo-[1,5-a]pyridin-3-yl,3,4-dihydro-1-benzopyran-2-yl, 3,4-dihydro-1-benzopyran-4-yl,3,4-dihydro-1-benzopyran-6-yl, indazol-3-yl,1,2,3,4-tetrahydro-2-isoquinolinyl; it should be understood that any ofthese ring systems may be substituted as defined in any of the otherembodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein Ar¹ is benzofuranyl, in particular2-benzofuranyl and/or 3-benzofuranyl; it should be understood that thebenzofuranyl ring system may be substituted as defined in any of theother embodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein one or more of the following heterocyclicgroups in the R² definition are restricted: 3,4,5,6-tetrahydropyranyl isrestricted to 3,4,5,6-tetrahydropyran-4-yl,3,4,5,6-tetrahydrothiopyranyl is restricted to3,4,5,6-tetrahydrothiopyran-4-yl, piperidinyl is restricted to1-piperidinyl or 4-piperidinyl;

it should be understood that any of these heterocyclic groups may besubstituted as defined in any of the other embodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein one or more of the following heterocyclicgroups in the R⁰ definition are restricted: piperidinyl is restricted to1-piperidinyl, morpholinyl is restricted to 1-morpholinyl, pyrazolyl isrestricted to 1-pyrazolyl, pyrrolidinyl is restricted to 1-pyrrolidinyl;

it should be understood that any of these heterocyclic groups may besubstituted as defined in any of the other embodiments.

In an embodiment, the present invention relates to those compounds offormula (I) and the pharmaceutically acceptable addition salts, and thesolvates thereof, or any subgroup thereof as mentioned in any of theother embodiments, wherein one or more of the heterocyclic groups in theAr¹, R² and R⁰ definitions are restricted as indicated in theembodiments hereabove.

In an embodiment, the present invention relates to compound of Formula(I), tautomers and stereoisomeric forms thereof, wherein:

R¹ is a ring system selected from the group consisting of imidazolyl,thienyl, piperidinyl, 4,5,6,7-tetrahydro-benzo[b]thienyl, benzofuranyl,2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, indazolyl;wherein said ring system is optionally substituted with one, two orthree substituents each independently selected from the group consistingof halo, C₁₋₄alkyl optionally substituted with one, two or threeindependently selected halo substituents, and C₁₋₄alkyloxy optionallysubstituted with one, two or three independently selected halosubstituents; in particular, wherein said ring system is optionallysubstituted with one, two or three substituents each independentlyselected from the group consisting of F, Cl, Br, CH₃, CF₃, CH₂CF₃,OCH(CH₃)₂, and OCF₃;

R² is hydrogen or methyl; in particular methyl;

Z is methylene;

L is C₁₋₃alkanediyl, in particular methylene, ethylidene or1,2-ethanediyl;

R³ is hydrogen;

R⁴ is methyl;

R⁵ is hydrogen;

X is CH;

and the pharmaceutically acceptable addition salts, and the solvatesthereof.

In an embodiment, the present invention relates to compound of Formula(I), tautomers and stereoisomeric forms thereof, wherein:

R¹ is a ring system selected from the group consisting of imidazol-1-yl,2-thienyl, 3-thienyl, 1-piperidinyl,4,5,6,7-tetrahydro-benzo[b]thien-3-yl,4,5,6,7-tetrahydro-benzo[b]thien-2-yl, 2-benzofuranyl, 3-benzofuranyl,2,3-dihydro-3-benzofuranyl, 2,3-dihydro-7-benzofuranyl,2,3-dihydro-2-benzofuranyl, 1,3-dihydro-1-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3-yl,4,5,6,7-tetrahydro-pyrazolo-[1,5-a]pyridin-3-yl,1,2,4-triazolo[4,3-a]pyridin-3-yl, pyrazolo[1,5-a]pyridin-3-yl,3,4-dihydro-1-benzopyran-2-yl, 3,4-dihydro-1-benzopyran-4-yl,3,4-dihydro-1-benzopyran-6-yl, indazol-3-yl;

wherein said ring system is optionally substituted with one, two orthree substituents each independently selected from the group consistingof halo, C₁₋₄alkyl optionally substituted with one, two or threeindependently selected halo substituents, and C₁₋₄alkyloxy optionallysubstituted with one, two or three independently selected halosubstituents; in particular, wherein said ring system is optionallysubstituted with one, two or three substituents each independentlyselected from the group consisting of F, Cl, Br, CH₃, CF₃, CH₂CF₃,OCH(CH₃)₂, and OCF₃;

R² is hydrogen or methyl; in particular methyl;

Z is methylene;

L is C₁₋₂alkanediyl, in particular methylene or ethylidene;

R³ is hydrogen;

R⁴ is methyl;

R⁵ is hydrogen;

X is CH;

and the pharmaceutically acceptable addition salts, and the solvatesthereof.

In an embodiment, the present invention relates to compound of Formula(I), tautomers and stereoisomeric forms thereof, wherein:

R¹ is 2-benzofuranyl or 3-benzofuranyl; substituted with one, two orthree substituents each independently selected from the group consistingof halo, C₁₋₄alkyl optionally substituted with one, two or threeindependently selected halo substituents, and C₁₋₄alkyloxy optionallysubstituted with one, two or three independently selected halosubstituents; in particular, said substituents are each independentlyselected from the group consisting of F, Cl, Br, CH₃, CF₃, CH₂CF₃,OCH(CH₃)₂, and OCF₃;

R² is hydrogen or methyl; in particular methyl;

Z is methylene;

L is C₁₋₂alkanediyl, in particular methylene or ethylidene;

R³ is hydrogen;

R⁴ is methyl;

R⁵ is hydrogen;

X is CH;

and the pharmaceutically acceptable addition salts, and the solvatesthereof.

In an embodiment, the present invention relates to compound of Formula(I), tautomers and stereoisomeric forms thereof, wherein:

R¹ is 2-benzofuranyl or 3-benzofuranyl, substituted with one or twosubstituents each independently selected from the group consisting ofhalo, and C₁₋₄alkyl substituted with one, two or three independentlyselected halo substituents; in particular, wherein said substituents areeach independently selected from the group consisting of F, Cl, and CF₃;

R² is methyl; in particular, wherein the carbon atom substituted with R²has the R configuration;

Z is methylene;

L is methylene or ethylidene;

R³ is hydrogen;

R⁴ is methyl;

R⁵ is hydrogen;

X is CH;

and the pharmaceutically acceptable addition salts, and the solvatesthereof.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of:

-   2-[[2,3-dihydro-4-(trifluoromethyl)-2-benzofuranyl]methyl]-3,4-dihydro-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione    (mixture of R and S),-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[(3-phenoxyphenyl)-methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-bromo-2-benzofuranyl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[[3-(cyclopropyloxy)-5-(trifluoromethyl)phenyl]methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[[3-(cyclopentyloxy)-4-methoxyphenyl]methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(2,3-dihydro-2,2-dimethyl-7-benzofuranyl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[5-(2,2,2-trifluoroethyl)-3-thienyl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[5-(trifluoromethyl)-3-thienyl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-bromo-2,3-dihydro-7-benzofuranyl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(4-bromo-2-thienyl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[2-[5-(2,2,2-trifluoroethyl)-3-thienyl]ethyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[[2,3-dihydro-4-(1-methylethoxy)-7-benzofuranyl]methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-yl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[5-(trifluoromethyl)-2-benzofuranyl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[2-(3,4-dihydro-2(1H)-isoquinolinyl)-2-oxoethyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-bromo-1,2-benzisothiazol-3-yl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(7-bromo-1,2-benzisothiazol-3-yl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[2-[3-(cyclopropyloxy)-5-(trifluoromethyl)phenyl]ethyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[5-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-chloro-1-methyl-1H-indazol-3-yl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-(1,2-benzisothiazol-3-ylmethyl)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-2-[[3-(1-methylethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl]methyl]-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-2-[[5-(1-methylethyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]methyl]-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[[1-[3-(cyclopropyloxy)-5-(trifluoromethyl)phenyl]cyclopropyl]methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[6-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-chloro-1,2-benzisoxazol-3-yl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(6-Bromo-3,4-dihydro-2H-chromen-2-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{[2-Chloro-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-2-[(5-Chloro-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1,2-benzisoxazol-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-Chloro-6-fluoro-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5,7-Dichloro-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[(5-Chloro-3-methyl-2,3-dihydro-1-benzofuran-3-yl)methyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(7-Bromo-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethoxy)-1-benzofuran-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethoxy)-1-benzofuran-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{(1R or    1S)-1-[5-(trifluoromethoxy)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{(1S or    1R)-1-[5-(trifluoromethoxy)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{[5-Fluoro-6-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{[6-Fluoro-5-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[6-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[1-(5-Chloro-6-fluoro-1-benzofuran-3-yl)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[7-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{(1R or    1S)-1-[6-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{(1S or    1R)-1-[6-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[(1S or    1R)-1-(5-Chloro-6-fluoro-1-benzofuran-3-yl)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[(1R or    1S)-1-(5-Chloro-6-fluoro-1-benzofuran-3-yl)ethyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-Chloro-6,7-difluoro-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{[5-Chloro-7-(trifluoromethyl)-1-benzofuran-3-yl]methyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{(1R or    1S)-1-[5-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   7-(4-Methyl-1H-imidazol-1-yl)-2-{(1S or    1R)-1-[5-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5-Chloro-7-fluoro-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[(5-Chloro-7-fluoro-1-benzofuran-3-yl)methyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(5,6-Dichloro-1-benzofuran-3-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[(5,6-Dichloro-1-benzofuran-3-yl)methyl]-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,    tautomers and stereoisomeric forms thereof,    and the pharmaceutically acceptable addition salts, and the solvates    thereof.

In an embodiment the compound of Formula (I) is selected from the groupconsisting of:

-   (3R)-2-{3-[(1R,5S)-3-Azabicyclo[3.1.0]hex-3-yl]-4-methylbenzyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{2-[3-(trifluoromethyl)piperidin-1-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1S or    1R)-1-[3-Hydroxy-5-(trifluoromethyl)phenyl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1R or    1S)-1-[3-(Cyclopropyloxy)-5-(trifluoromethyl)phenyl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1S or    1R)-1-[3-(Cyclopropyloxy)-5-(trifluoromethyl)phenyl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1R or    1S)-1-[3-Hydroxy-4-(trifluoromethoxy)phenyl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1S or    1R)-1-[3-Hydroxy-4-(trifluoromethoxy)phenyl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-({2-[3-(trifluoromethyl)piperidin-1-yl]-1,3-thiazol-4-yl}methyl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{(3R and    3S)-2-oxo-1-[3-(trifluoromethyl)phenyl]pyrrolidin-3-yl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione    (mixture of diastereomers),-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(1R or    1S)-1-methyl-6-(trifluoromethyl)-1,3-dihydro-2-benzofuran-1-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(1S or    1R)-1-methyl-6-(trifluoromethyl)-1,3-dihydro-2-benzofuran-1-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(6-Bromo-2-methyl-3,4-dihydro-2H-chromen-2-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[6-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(5R or 5    S)-5-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]methyl}-3,4-dihydro-2H-pyrido-[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(5S or    5R)-5-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl]methyl}-3,4-dihydro-2H-pyrido-[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[6-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-3,4-dihydro-2H-pyrido-[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(6R or    6S)-6-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(6S or    6R)-6-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[5,7-Bis(trifluoromethyl)-2,3-dihydro-1-benzofuran-3-yl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(6R or    6S)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(6S or    6R)-6-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(5R or 5    S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(5S or    5R)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{2-oxo-2-[3-(trifluoromethyl)-piperidin-1-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(5R or 5    S)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{[(5S or    5R)-5-(trifluoromethyl)-4,5,6,7-tetrahydro-1-benzothiophen-2-yl]methyl}-3,4-dihydro-2H-pyrido[1,2-a]-pyrazine-1,6-dione,-   (3R)-2-[(6-Chloro-3,4-dihydro-2H-chromen-4-yl)methyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(1R or    1S)-1-(5-Chloro-6-fluoro-1-benzofuran-3-yl)ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(1S or    1R)-1-(5-Chloro-6-fluoro-1-benzofuran-3-yl)ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{(1R or    1S)-1-[5-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{(1S or    1R)-1-[5-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{(1R or    1S)-1-[5-(trifluoromethoxy)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{(1S or    1R)-1-[5-(trifluoromethoxy)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1R or    1S)-1-[5-Fluoro-6-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1S or    1R)-1-[5-Fluoro-6-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-3-Methyl-7-(4-methyl-1H-imidazol-1-yl)-2-{(1S)-1-[6-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1R or    1S)-1-[6-Fluoro-5-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-{(1S or    1R)-1-[6-Fluoro-5-(trifluoromethyl)-1-benzofuran-3-yl]ethyl}-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(1R or    1S)-1-(5-Chloro-1-benzofuran-3-yl)ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(1S or    1R)-1-(5-Chloro-1-benzofuran-3-yl)ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(1S or    1R)-1-(5-Chloro-7-fluoro-1-benzofuran-3-yl)ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   (3R)-2-[(1R or    1S)-1-(5-Chloro-7-fluoro-1-benzofuran-3-yl)ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-dione,    tautomers and stereoisomeric forms thereof,    and the pharmaceutically acceptable addition salts, and the solvates    thereof

In an embodiment the compound of Formula (I) is selected from the groupconsisting of:

-   2-[[3-(3-azabicyclo[3.1.0]hex-3-yl)-4-methylphenyl]methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[2-[3-(trifluoromethyl)-1-piperidinyl]ethyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-2-[1-[3-hydroxy-5-(trifluoromethyl)phenyl]ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[1-[3-(cyclopropyloxy)-5-(trifluoromethyl)phenyl]ethyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-2-[1-[3-hydroxy-4-(trifluoromethoxy)phenyl]ethyl]-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[2-[3-(trifluoromethyl)-1-piperidinyl]-4-thiazolyl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[2-oxo-1-[3-(trifluoromethyl)phenyl]-3-pyrrolidinyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[[1,3-dihydro-1-methyl-6-(trifluoromethyl)-1-isobenzofuranyl]methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[(6-bromo-3,4-dihydro-2-methyl-2H-1-benzopyran-2-yl)methyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[4,5,6,7-tetrahydro-6-(trifluoromethyl)benzo[b]thien-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[4,5,6,7-tetrahydro-5-(trifluoromethyl)benzo[b]thien-2-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[4,5,6,7-tetrahydro-5-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[5,6,7,8-tetrahydro-6-(trifluoromethyl)-1,2,4-triazolo[4,3-a]pyridin-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   2-[2,3-dihydro-5,7-bis(trifluoromethyl)-3-benzofuranyl]-3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2H-pyrido[1,2-a]pyrazine-1,6-dione,-   3,4-dihydro-3-methyl-7-(4-methyl-1H-imidazol-1-yl)-2-[[4,5,6,7-tetrahydro-5-(trifluoromethyl)benzo[b]thien-3-yl]methyl]-2H-pyrido[1,2-a]pyrazine-1,6-dione,    tautomers and stereoisomeric forms thereof,    and the pharmaceutically acceptable addition salts, and the solvates    thereof

All possible combinations of the above-indicated interesting embodimentsare considered to be embraced within the scope of this invention.

Preparation of the Compounds

The present invention also encompasses processes for the preparation ofcompounds of Formula (I), intermediates and subgroups thereof. Theperson skilled in the art will notice that in the reactions described,it can be necessary to protect reactive functional groups, for examplehydroxy, amino, or carboxy groups, where these are desired in the finalproduct, to avoid their unwanted participation in the reactions.Conventional protecting groups can be used in accordance with standardpractice, for example, see T. W. Greene and P. G. M. Wuts in “ProtectiveGroups in Organic Chemistry”, John Wiley and Sons, 1999.

Alternatively, in the presence of reactive functional groups, the personskilled in the art may consider tuning the general reaction conditionson the basis of standard chemistry knowledge, to avoid undesired sidereactions.

When several methods are described to obtain the same structure, thechoice of a method over another one may also minimize unwanted sidereactions.

The compounds of Formula (I) and the subgroups thereof can be preparedby a succession of steps as described hereunder. They are generallyprepared from starting materials which are either commercially availableor prepared by standard means obvious to those skilled in the art. Thecompounds of the present invention can be also prepared using standardsynthetic processes commonly used by those skilled in the art of organicchemistry.

The skilled person will realize that in some reactions microwave heatingmay be used instead of conventional heating to shorten the overallreaction time.

The general preparation of some typical examples is shown below. All thevariables are defined as described in the scope of the invention unlessotherwise mentioned or unless a context dictates otherwise. In thefollowing examples, R^(1a) is phenyl, p-methoxyphenyl, Ar¹ or Ar²,unless otherwise mentioned or unless a context dictates otherwise.

Experimental Procedures Scheme 1

Experimental Procedure 1

An intermediate of formula (III), wherein all the variables are definedas described in the scope of the invention, can be prepared vianucleophilic substitution by an intermediate of formula (II-a) on anappropriate electrophile, such as for example an alkyl halide, such asfor example an alkyl iodide, with methods known to the person skilled inthe art, such as for example refluxing the mixture of nucleophile andelectrophile in the presence or absence of solvent. Inert atmosphere mayenhance the reaction outcome.

Alternatively, intermediate (III) can be obtained by reductiveamination, starting from the appropriate aminoalcohol (II-b), in thepresence of the desired carbonyl compound, such as for example a ketoneor an aldehyde. The reaction can be typically performed in the presenceof a suitable solvent, such as MeOH (methanol) and a reducing agent,such as NaBH₄ (sodium borohydride) or NaCNBH₃ (sodium cyanoborohydride).Pre-stirring of the mixture in the absence of the reducing agent underheating, and subsequent addition of the reducing agent at lowertemperature, can enhance the reaction outcome.

Alternatively, intermediate (III) can be obtained by manipulation of anysuitable precursor by methods known to the person skilled in the art,such as reduction of the corresponding α-aminoacid, for example by usingborane-methyl sulphide in the presence of a suitable solvent, such asTHF (tetrahydrofuran). Precooling of the reaction mixture, followed byheating after the addition of all the reagents, may enhance the reactionoutcome.

Experimental Procedure 2

An intermediate of formula (V), wherein all the variables are defined asdescribed in the scope of the invention, can be obtained via protectionof the alcohol functionality of intermediate (III). The protection canbe for example a silylation, that can be performed in the presence of asuitable solvent, such as DCM (dichloromethane), an additive, such asimidazole, and a silylating agent, such as TBSC1(tert-butyldimethylsilyl chloride) or TMSC1 (trimethylsilyl chloride),following standard conditions known to the person skilled in the art.

Alternatively, intermediate (V) can be obtained by reductive aminationof an appropriate amine (II-a) with a carbonyl intermediate such as(IV), where for example PG (the protecting group) can betert-butyldimethylsilyl. Typical conditions involve stirring of thereagents in a suitable solvent, such as DCE (1,2-dichloroethane), in thepresence of a reducing agent, such as NaBH(OAc)₃ (sodiumtriacetoxyborohydride). The person skilled in the art will notice thatintermediate (V) can also be obtained via standard reductive aminationconditions, starting from an intermediate of structure (II-b), where Ris the desired protecting group (PG).

Experimental Procedure 3

An intermediate of formula (VII), wherein

PG is a protecting group;

and all the other variables are defined as described in the scope of theinvention, can be obtained via acylation of intermediate (V) with anintermediate of structure (VI), where

R¹² is hydrogen or bromine;

R¹⁰ is hydroxyl or chlorine.

Structure (VI) is hereby named (VI-a) when R¹⁰ is hydroxyl, and (VI-b)when R¹⁰ is a chlorine. Acylation using intermediate (VI-a) can beperformed for example under classical peptide synthesis conditions.Typically, the reaction requests stirring of the starting materials (V)and (VI-a) in the presence of a base, such as DIPEA (diisopropylethylamine) and a peptide coupling reagent, such as HBTU(O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate), ina suitable solvent, such as DMF (N,N-dimethyl formamide).

Alternatively, acylation can be achieved by reacting intermediate (V)with an intermediate of formula (VI-b). The reaction can be performedfor example by stirring the starting materials in the presence of abase, such as DIPEA, in a suitable solvent, such as DMF.

Experimental Procedure 4

An intermediate of formula (VIII), wherein

R¹² is hydrogen or bromine;

and all the other variables are defined as described in the scope of theinvention, can be obtained by deprotection of intermediate (VII), bymethods known to the person skilled in the art. In the case of a silylprotecting group, for example, one standard method would be treatingintermediate (VII), dissolved in a suitable solvent, such as THF, with afluoride source, such as TBAF (tetrabutylammonium fluoride).

Alternatively, an intermediate of formula (VIII) can be obtained bydirect acylation of a suitable aminoalcohol of structure (III) with anacid of structure (VI-a). The reaction can be performed for exampleunder peptide coupling conditions, in the presence of a base, such asDIPEA, and a peptide coupling reagent, such as HBTU, in a suitablesolvent, such as DMF.

Experimental Procedures Scheme 2

Experimental Procedure 5

An intermediate of formula (IX), wherein

R¹² is hydrogen or bromine;

and all the other variables are defined as described in the scope of theinvention, can be obtained by debenzylation of intermediate (VIII),using standard methods known to the person skilled in the art. Forexample, the benzylation can be achieved by stirring a solution ofintermediate (VIII) in a suitable solvent, such as MeOH or MeOH/THF, andin the presence of a hydrogenation catalyst, such as 10% Pd/C (palladiumon carbon), under hydrogen atmosphere.

Alternatively, intermediate (IX) can be obtained by amide synthesisstarting from a suitable ester, such as intermediate (XI), where R¹¹ isfor example a methyl group. Typical conditions involve stirring asolution of the ester in a suitable solvent, such as MeOH, in thepresence of a desired aminoalcohol of structure (III) under reflux.Alternatively, starting as well from intermediate (XI), intermediate(IX) can be obtained by using a 2-step method. First, ester (XI) can besaponified to give intermediate (XII), where M is a metal. The reactioncan be performed for example by adding an hydroxide, such as LiOH(lithium hydroxide), to a solution of ester (XI) in a suitable polarsolvent or in a mixture of miscible solvents of which one is highlypolar, such as THF and water. Heating the reaction mixture can enhancethe reaction outcome. In the second step, intermediate (XII) can bereacted with an aminoalcohol of structure (III), to afford intermediate(IX). Typically, peptide coupling conditions can be applied, such asstirring the starting material, dissolved in a suitable solvent, such asDMF, in the presence of a peptide coupling agent, such as HBTU. Theskilled in the art will appreciate that when a base, such as DIPEA, ispresent in the mixture, the reaction affords directly the cyclisedintermediate (XVII). Heating the reaction mixture can enhance thereaction outcome.

Alternatively, intermediate (IX) can be obtained starting from acid (X),using for example standard peptide coupling conditions, such as stirringintermediate (X) and the desired aminoalcohol (III), dissolved in asuitable solvent, such as DMF, in the presence of a peptide couplingreagent, such as HBTU.

Alternatively, intermediate (IX) can be obtained by using a 3-stepsynthesis starting from intermediate (VIII). First, the free alcoholfunctionality can be protected using standard protection methods, suchas for example acylation to the ester. Typical conditions would be forexample treating intermediate (VIII) with a suitable acylating agent,such as a combination of acetic anhydride and DMAP(dimethylaminopyridine), in the presence of a base, such as Et₃N(triethylamine) in a suitable inert solvent, such as DCM. The soobtained intermediate (XIII) can subsequently undergo debenzylationusing standard deprotection methods, such as stirring in a suitablesolvent, such as MeOH, under hydrogen atmosphere in the presence of ahydrogenation catalyst, such as 10% Pd/C. Pyridone intermediate (XIV)can be finally converted into intermediate (IX) by using one of theavailable deprotection methods for the chosen protecting group. In thecase of protection of the alcohol as an ester, saponification using abase, such as NaOH (sodium hydroxide) in a suitable solvent, such asMeOH, can afford the desired free alcohol (IX). The skilled in the artwill recognize that this method is valuable when the alcoholfunctionality present in intermediate (VIII) could be liable underdebenzylation conditions.

Experimental Procedure 6

An intermediate of formula (XVII), wherein

R¹² is hydrogen or bromine;

and all the other variables are defined as described in the scope of theinvention, can be obtained via intramolecular cyclization, for exampleby applying Mitsunobu conditions to intermediate (IX). The reaction canbe performed by treating a solution of intermediate (IX) in a suitableinert and dry solvent, such as THF, with an azadicarboxylate species,such as DIAD (diisopropyl azodicarboxylate), in the presence of aphosphine, such as triphenylphosphine, under inert atmosphere.Precooling of the solution may be used.

Alternatively, starting from intermediate (VIII) a 3-step method can beused. First, the free hydroxyl function in intermediate (VIII) can beconverted into a suitable leaving group. For example, intermediate(XV-a), where LG=chlorine, can be obtained under mild conditions bydissolving intermediate (VIII) in a suitable solvent, such as DCM, andtreating it with a chlorinating agent, such as thionyl chloride.Precooling of the solution before addition of the chlorinating agent canenhance the outcome of the reaction. Intermediate (XV) can then undergodebenzylation to give intermediate (XVI), using standard methodscompatible with the presence of the leaving group. In the case ofintermediate (XV-a), for example, debenzylation can be achieved bytreating the intermediate, dissolved in a suitable and inert solvent,such as DCM, with a Lewis acid such as BBr₃ (boron tribromide).Precooling of the reaction mixture before addition of the Lewis acid canenhance the reaction outcome. Finally, intermediate (XVI) can beprocessed to intermediate (XVII) by using standard substitutionconditions. For example, starting from intermediate (XVI-a), whereLG=chlorine, the ring closure can be achieved by treating the substrate,dissolved in a suitable solvent, such as DMF, with a base, such as NaH(sodium hydride). Precooling of the reaction and a level of dilutionhigh enough to avoid intermolecular reactions can enhance the reactionoutcome.

Experimental Procedures Scheme 3

Experimental Procedure 7

An intermediate of formula (XVIII-b), wherein all the variables aredefined as described in the scope of the invention, can be obtained froman intermediate of structure (XVII-b), where all the variables aredefined as mentioned hereabove, with the exception of the residual-L-R^(1a), defined for structure (XVII-b) as any kind of protectinggroup suitable for an amidic nitrogen, such as, but not restricted to, abenzyl group (L=CH₂, R^(1a) phenyl) or a PMB group (p-methoxybenzyl,L=CH₂, R^(1a)=p-methoxyphenyl).

Intermediate (XVII-b) can be converted into intermediate (XVIII-b) bymeans of deprotection methods known to the person skilled in the art.For example, when L=CH₂, R^(1a) phenyl, deprotection can be achieved bytreating intermediate (XVII-b), dissolved in a suitable solvent, such asdry toluene, with a strong acid, such as TfOH (trifluoromethansulfonicacid). Heating the reaction mixture under stirring can enhance thereaction outcome.

Experimental Procedure 8

An intermediate of formula (XVII-b), wherein all the variables aredefined as described in the scope of the invention, can be obtained fromintermediate (XVIII-b) by means of any manipulation known to the personskilled in the art for the functionalization of an amidic nitrogen. Twogeneral examples are reported:

Example 1

When

R^(1a) is attached to the remainder of the molecule on an aromaticcarbon;

L is a covalent bond;

functionalization can be achieved for example by means of a coppercatalyzed C—N coupling. Standard conditions, such as stirring a mixtureof intermediate (XVIII-b), dissolved in a suitable solvent, such as DMF,in the presence of a base, such as K₃PO₄ (potassium phosphate), aligand, such as N,N′-dimethyl-1,2-cyclohexanediamine, an aryl halide anda copper catalyst, such as CuI, could be used. Degassing the reactionmixture with an inert gas, such as N₂ or argon, and heating the reactionmixture to high temperatures, such as reflux temperature, may enhancethe reaction outcome.

Example 2

When

L is one of the variables described in the scope of the invention,

with the exception of L being a covalent bond if R^(1a) is attached tothe remainder of the molecule on an aromatic carbon;

functionalization can be achieved for example by treating intermediate(XVIII-b), dissolved in a suitable and inert solvent, such as DMF, witha base, such as NaH, followed by addition of an electrophile. Precoolingof the reaction mixture can enhance the reaction outcome.

Experimental Procedure 9

An intermediate of formula (XVIII-a), wherein all the variables aredefined as described in the scope of the invention, can be obtained froman intermediate of structure (XVII-a), where all the variables aredefined as mentioned hereabove, with the exception of

the residual -L-R^(1a), defined for structure (XVII-a) as any kind ofprotecting group suitable for an amidic nitrogen, such as, but notrestricted to, a benzyl group (L=CH₂, R^(1a) phenyl) or a PMB group(p-methoxybenzyl, L=CH₂, R^(1a) p-methoxyphenyl).

Intermediate (XVII-a) can be converted into intermediate (XVIII-a) bymeans of deprotection methods known to the person skilled in the art.For example, when L=CH₂, R^(1a) phenyl, deprotection can be achieved bytreating intermediate (XVII-a), dissolved in a suitable solvent, such asdry toluene, with a strong acid, such as TfOH. Heating the reactionmixture under stirring can enhance the reaction outcome. Alternatively,an intermediate of formula (XVIII-a) can be obtained starting from anintermediate of formula (XVIII-b) by means of direct bromination.Different brominating agents can be used. For example, the reaction canbe performed by dissolving intermediate (XVIII-b) in a mixture ofsolvents such as DCM/AcOH (acetic acid) and adding bromine to themixture, or by adding NBS (N-bromosuccinimide) to a solution ofintermediate (XVIII-b) in an appropriate solvent, such as acetonitrile.The reaction mixture may be stirred under heating and inert atmosphere.

Experimental Procedure 10

An intermediate of formula (XVII-a), wherein all the variables aredefined as described in the scope of the invention, can be obtained fromintermediate (XVIII-a) by means of any manipulation known to the personskilled in the art for the functionalization of an amidic nitrogen. Onegeneral example is reported:

Example 1

When

L is one of the variables described in the scope of the invention,

with the exception of L being a covalent bond if R^(1a) is attached tothe remainder of the molecule on an aromatic carbon;

functionalization can be achieved for example by treating intermediate(XVIII-a), dissolved in a suitable and inert solvent, such as DMF, witha base, such as NaH, followed by an electrophile. Precooling of thereaction mixture can enhance the reaction outcome.

Alternatively, intermediate (XVII-a) can be obtained by directbromination of intermediate (XVII-b), for example by adding bromine to asolution of intermediate (XVII-b), dissolved in a mixture of solventssuch as DCM/AcOH.

Experimental Procedures Scheme 4

Experimental Procedure 11

A compound of formula (I), wherein all the variables are defined asdescribed in the scope of the invention, can be obtained for example bycopper catalyzed C—N coupling. Standard conditions involve stirring ofintermediate (XVII-a) in the presence of a copper catalyst, such as CuI,a base, such as Cs₂CO₃ (cesium carbonate), the coupling partner, such asfor example 4-methylimidazole, and a ligand, such asN,N′-dimethyl-1,2-cyclohexanediamine, in a suitable solvent, such asDMF. Degassing the reaction mixture with an inert gas, such as N₂ orargon, and heating the reaction mixture to high temperatures, such asreflux temperature, may enhance the reaction outcome.

Alternatively, a compound of formula (I), where R⁵ is restricted tohydrogen, can be obtained by palladium catalyzed C—N coupling.Typically, an intermediate of formula (XVII-a) is stirred and heated inthe presence of a base, such as K₃PO₄, a palladium source, such asPd₂(dba)₃ (tris(dibenzylideneacetone)dipalladium(0)), a ligand, such as2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyland the desired imidazole, in the presence of a solvent or a mixture ofsolvents, such as toluene/dioxane. Premixing of the catalyst and theligand followed by heating before addition of the remaining reagents,degassing of the solution and heating can enhance the reaction outcome.

Alternatively, a compound of formula (I) can be obtained via a 5-stepsynthesis. In the first step, intermediate (XVII-a) can be convertedinto intermediate (XX), where PG is a mono or divalent nitrogenprotecting group. For example, when PG=acetyl, the reaction can beperformed using known amide coupling methodologies. For example,acetamide can be reacted with intermediate (XVII-a) in the presence of abase, such as K₃PO₄, a palladium source, such as Pd₂(dba)₃, a ligand,such as (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine](Xantphos), in a suitable solvent, such as dry THF. Degassing of thereaction mixture during the set-up with an inert gas, such as N₂ orargon, anhydrous conditions, and the use of high temperatures, such asreflux temperature, can enhance the reaction outcome. In the secondstep, intermediate (XX) can be converted into the free amineintermediate (XXI) by using any deprotection method tolerated by theother functionalities present in the molecule. For example, when PG inintermediate (XX)=acetyl, an acidic hydrolysis, using for example HCl(hydrochloric acid), in a suitable solvent, such as MeOH, can be used.In the third step, the amino group in intermediate (XXI) can be acylatedto give intermediate (XXII). For example, if R⁵ in compound (XVII)represents hydrogen, formylation of intermediate (XXI) can be obtainedby adding to intermediate (XXI), dissolved in a suitable inert solvent,such as THF, a formylating agent, such as a mixture of acetic anhydrideand formic acid. Stirring of the reaction under heating can enhance thereaction outcome. In the fourth step, intermediate (XXII) can beconverted to the cyclization precursor (XXIII) with methodologies knownto the person skilled in the art and depending on the desiredfunctionalities X and R⁴. For example, if in compound (XVII) X═CH andR⁴=alkyl, the reaction can be performed by adding the desiredα-haloketone, such as for example 1-bromo-2-butanone, to a mixture ofintermediate (XXII), and a base, such as K₂CO₃, in a suitable solvent,such as DMF. If the halogen of the α-haloketone is different fromiodine, the reaction can be improved by means of an in-situ Filkensteinreaction, performed by adding an iodine salt, such as KI, to thereaction mixture. Finally, intermediate (XXIII) can be converted intocompound (I) by means of a classical imidazole synthesis. Diketoprecursor (XXIII) can be cyclized into desired compound (I) in thepresence of a nitrogen source, such as ammonium acetate, and an acid,such as AcOH. Heating the reaction to reflux temperature can enhance thereaction outcome.

Alternatively, when the residual -L-R^(1a) in compound (I) correspondsto any kind of protecting group suitable for an amidic nitrogen, suchas, but not restricted to, a benzyl group (L=CH₂, R^(1a)=phenyl) or aPMB group (p-methoxybenzyl, L=CH₂, R^(1a)=p-methoxyphenyl), the compoundcan be further converted via a two-step method to generate otherstructures that can be described as well with the general formula (I).In the first step, compound (I) can be converted into intermediate(XXIV) by means of deprotection methods known to the person skilled inthe art. For example, when L=CH₂, R^(1a)=p-methoxyphenyl, deprotectioncan be achieved by treating compound (I), dissolved in a suitablesolvent, such as dry toluene, with a strong acid, such as TfOH. Heatingthe reaction mixture under stirring can enhance the reaction outcome. Inthe second step, intermediate (XXIV) can be converted to a compound ofgeneral formula (I), by means of known N-functionalization methods.

For example, when

L is one of the variables described in the scope of the invention,

with the exception of L being a covalent bond if R^(1a) is attached tothe remainder of the molecule on an aromatic carbon;

one possibility would be treating intermediate (XXIV), dissolved in asuitable and inert solvent, such as DMF, with a base, such as NaH,followed by an electrophile.

Precooling of the reaction mixture and anhydrous conditions can enhancethe reaction outcome.

Alternatively, intermediate (XVII-a) wherein R³ is restricted to halo(halo=Cl, Br, I), hereby called intermediate (XVII-b), may be obtainedstarting from intermediate (XVII-a) wherein R³ is restricted tohydrogen, hereby called (XVII-a1), via a halogenation reaction. Forexample, if halo is Cl in intermediate (XVII-b), the reaction can beperformed by treating intermediate (XVII-a1), dissolved in a suitablesolvent, such as DMF, with a chlorine source, such as NCS(N-chlorosuccinimide).

Alternatively, a compound of formula (I) bearing an R^(1a) group whichcan undergo further manipulation, could be converted into othercompounds described as well with the general formula (I), by mean of oneor several subsequent chemical transformations known to the personskilled in the art. For example, if R^(1a) is an halogenated ringsystem, the corresponding dehalogenated compound can be obtained bystirring a solution of compound (I) in a suitable solvent, such as MeOHor MeOH/THF, and in the presence of a hydrogenation catalyst, such as10% Pd/C (palladium on carbon), under hydrogen atmosphere. Heating thereaction mixture or a high pressure of hydrogen can enhance the reactionoutcome.

Starting materials can be obtained commercially or can be prepared bythose skilled in the art.

Where necessary or desired, any one or more of the following furthersteps in any order may be performed:

Compounds of Formula (I) and any subgroup thereof may be converted intofurther compounds of Formula (I) and any subgroup thereof, usingprocedures known in the art.

It will be appreciated by those skilled in the art that in the processesdescribed above the functional groups of intermediate compounds may needto be blocked by protecting groups. In case the functional groups ofintermediate compounds were blocked by protecting groups, they can bedeprotected after a reaction step.

In all these preparations, the reaction products may be isolated fromthe reaction medium and, if necessary, further purified according tomethodologies generally known in the art such as, for example,extraction, crystallization, trituration and chromatography. Inparticular, stereoisomers can be isolated chromatographically using achiral stationary phase such as, for example, Chiralpak® AD (amylose 3,5dimethyl-phenyl carbamate) or Chiralpak® AS, both purchased from DaicelChemical Industries, Ltd, in Japan, or by Supercritical FluidChromatography (SFC).

The chirally pure forms of the compounds of Formula (I) form a preferredgroup of compounds. It is therefore that the chirally pure forms of theintermediates and their salt forms are particularly useful in thepreparation of chirally pure compounds of Formula (I). Also enantiomericmixtures of the intermediates are useful in the preparation of compoundsof Formula (I) with the corresponding configuration.

Pharmacology

It has been found that the compounds of the present invention modulatethe γ-secretase activity. The compounds according to the invention andthe pharmaceutically acceptable compositions thereof therefore may beuseful in the treatment or prevention of AD, TBI, dementia pugilistica,MCI, senility, dementia, dementia with Lewy bodies, cerebral amyloidangiopathy, multi-infarct dementia, Down's syndrome, dementia associatedwith Parkinson's disease and dementia associated with beta-amyloid;preferably AD.

The compounds according to the present invention and thepharmaceutically acceptable compositions thereof may be useful in thetreatment or prevention of a disease or condition selected from thegroup consisting of AD, TBI, dementia pugilistica, MCI, senility,dementia, dementia with Lewy bodies, cerebral amyloid angiopathy,multi-infarct dementia, Down's syndrome, dementia associated withParkinson's disease and dementia associated with beta-amyloid.

A skilled person will be familiar with alternative nomenclatures,nosologies, and classification systems for the diseases or conditionsreferred to herein. For example, the fifth edition of the Diagnostic &Statistical Manual of Mental Disorders (DSM-5™) of the AmericanPsychiatric Association utilizes terms such as neurocognitive disorders(NCDs) (both major and mild), in particular, neurocognitive disordersdue to Alzheimer's disease, due to traumatic brain injury (TBI), due toLewy body disease, due to Parkinson's disease or to vascular NCD (suchas vascular NCD present with multiple infarctions). Such terms may beused as an alternative nomenclature for some of the diseases orconditions referred to herein by the skilled person.

As used herein, the term “modulation of γ-secretase activity” refers toan effect on the processing of APP by the γ-secretase-complex.Preferably it refers to an effect in which the overall rate ofprocessing of APP remains essentially as without the application of saidcompounds, but in which the relative quantities of the processedproducts are changed, more preferably in such a way that the amount ofthe Aβ42-peptide produced is reduced. For example a different Abetaspecies can be produced (e.g. Abeta-38 or other Abeta peptide species ofshorter amino acid sequence instead of Abeta-42) or the relativequantities of the products are different (e.g. the ratio of Abeta-40 toAbeta-42 is changed, preferably increased).

It has been previously shown that the γ-secretase complex is alsoinvolved in the processing of the Notch-protein. Notch is a signalingprotein which plays a crucial role in developmental processes (e.g.reviewed in Schweisguth F (2004) Curr. Biol. 14, R129). With respect tothe use of γ-secretase modulators in therapy, it seems particularlyadvantageous not to interfere with the Notch-processing activity of theγ-secretase activity in order to avoid putative undesired side-effects.While γ-secretase inhibitors show side effects due to concomitantinhibition of Notch processing, γ-secretase modulators may have theadvantage of selectively decreasing the production of highlyaggregatable and neurotoxic forms of Aβ, i.e. Aβ42, without decreasingthe production of smaller, less aggregatable forms of Aβ, i.e. Aβ38 andwithout concomitant inhibition of Notch processing. Thus, compounds arepreferred which do not show an effect on the Notch-processing activityof the γ-secretase-complex.

As used herein, the term “treatment” is intended to refer to allprocesses, wherein there may be a slowing, interrupting, arresting, orstopping of the progression of a disease, or an alleviation of symptoms,but does not necessarily indicate a total elimination of all symptoms.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is or has been the object oftreatment, observation or experiment.

The invention relates to compounds according to the general Formula (I),and the pharmaceutically acceptable acid or base addition salts and thesolvates thereof, for use as a medicament.

The invention also relates to compounds according to the general Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, for use in the modulation of γ-secretase activity.

The invention also relates to compounds according to the general Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, for use in the treatment or prevention of diseasesor conditions selected from the group consisting of AD, TBI, dementiapugilistica, MCI, senility, dementia, dementia with Lewy bodies,cerebral amyloid angiopathy, multi-infarct dementia, Down's syndrome,dementia associated with Parkinson's disease and dementia associatedwith beta-amyloid.

In an embodiment, said disease or condition is preferably AD.

The invention also relates to compounds according to the general Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof for use in the treatment or prevention of a diseaseor condition selected from neurocognitive disorder due to Alzheimer'sdisease, neurocognitive disorder due to traumatic brain injury,neurocognitive disorder due to Lewy body disease, neurocognitivedisorder due to Parkinson's disease or vascular neurocognitive disorder.

The invention also relates to compounds according to the general Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, for use in the treatment of said diseases.

The invention also relates to compounds according to the general Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, for the treatment or prevention of said diseases.

The invention also relates to compounds according to the general formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, for the treatment or prevention, in particulartreatment, of γ-secretase mediated diseases or conditions.

The invention also relates to the use of compounds according to thegeneral Formula (I), and the pharmaceutically acceptable acid or baseaddition salts and the solvates thereof, for the manufacture of amedicament.

The invention also relates to the use of compounds according to thegeneral Formula (I), and the pharmaceutically acceptable acid or baseaddition salts and the solvates thereof, for the manufacture of amedicament for the modulation of γ-secretase activity.

The invention also relates to the use of compounds according to thegeneral Formula (I), and the pharmaceutically acceptable acid or baseaddition salts and the solvates thereof, for the manufacture of amedicament for the treatment or prevention of any one of the diseaseconditions mentioned hereinbefore.

The invention also relates to the use of compounds according to thegeneral Formula (I), and the pharmaceutically acceptable acid or baseaddition salts and the solvates thereof, for the manufacture of amedicament for the treatment of any one of the disease conditionsmentioned hereinbefore.

In the invention, particular preference is given to compounds of Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, or any subgroup thereof with a IC₅₀ value for theinhibition of the production of Aβ42-peptide of less than 1000 nM,preferably less than 100 nM, more preferably less than 50 nM, even morepreferably less than 20 nM as determined by a suitable assay, such asthe assay used in the Examples below.

The compounds of Formula (I), and the pharmaceutically acceptable acidor base addition salts and the solvates thereof, can be administered tomammals, preferably humans for the treatment or prevention of any one ofthe diseases mentioned hereinbefore.

In view of the utility of the compounds of Formula (I), and thepharmaceutically acceptable acid or base addition salts and the solvatesthereof, there is provided a method of treating a subject, in particularwarm-blooded animals, including humans, suffering from or a method ofpreventing a subject, in particular warm-blooded animals, includinghumans, to suffer from any one of the diseases mentioned hereinbefore.

Said methods comprise the administration, i.e. the systemic or topicaladministration, preferably oral administration, of a therapeuticallyeffective amount of a compound of Formula (I), and the pharmaceuticallyacceptable acid or base addition salts and the solvates thereof, to asubject, in particular warm-blooded animals, including humans.

Therefore, the invention also relates to a method of treating orpreventing a disease or condition selected from Alzheimer's disease,traumatic brain injury, mild cognitive impairment, senility, dementia,dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarctdementia, dementia pugilistica, Down's syndrome, dementia associatedwith Parkinson's disease and dementia associated with beta-amyloid,comprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound or a pharmaceutical composition accordingto the invention.

The invention also relates to a method of treating or preventing adisease or condition selected from neurocognitive disorder due toAlzheimer's disease, neurocognitive disorder due to traumatic braininjury, neurocognitive disorder due to Lewy body disease, neurocognitivedisorder due to Parkinson's disease or vascular neurocognitive disorder,comprising administering to a subject in need thereof, a therapeuticallyeffective amount of a compound or a pharmaceutical composition accordingto the invention.

The present invention also concerns to the use of compounds of Formula(I), and the pharmaceutically acceptable acid or base addition salts andthe solvates thereof, for the modulation of γ-secretase activityresulting in a decrease in the relative amount of Aβ42-peptidesproduced.

An advantage of the compounds or a part of the compounds of the presentinvention may be their enhanced CNS-penetration.

Those of skill in the treatment of such diseases could determine theeffective therapeutic daily amount from the test results presentedhereinafter. An effective therapeutic daily amount would be from about0.005 mg/kg to 50 mg/kg, in particular 0.01 mg/kg to 50 mg/kg bodyweight, more in particular from 0.01 mg/kg to 25 mg/kg body weight,preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably fromabout 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1mg/kg body weight. The amount of a compound according to the presentinvention, also referred to here as the active ingredient, which isrequired to achieve a therapeutically effect will of course, vary oncase-by-case basis, for example with the particular compound, the routeof administration, the age and condition of the recipient, and theparticular disorder or disease being treated.

A method of treatment may also include administering the activeingredient on a regimen of between one and four intakes per day. Inthese methods of treatment the compounds according to the invention arepreferably formulated prior to administration. As described hereinbelow, suitable pharmaceutical formulations are prepared by knownprocedures using well known and readily available ingredients.

The compounds of the present invention, that can be suitable to treat orprevent Alzheimer's disease or the symptoms thereof, may be administeredalone or in combination with one or more additional therapeutic agents.Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a compound of Formula (I), apharmaceutically acceptable acid or base addition salt, or a solvatethereof, and one or more additional therapeutic agents, as well asadministration of the compound of Formula (I), a pharmaceuticallyacceptable acid or base addition salt, or a solvate thereof, and eachadditional therapeutic agents in its own separate pharmaceutical dosageformulation. For example, a compound of Formula (I), a pharmaceuticallyacceptable acid or base addition salt, or a solvate thereof, and atherapeutic agent may be administered to the patient together in asingle oral dosage composition such as a tablet or capsule, or eachagent may be administered in separate oral dosage formulations.

While it is possible for the active ingredient to be administered alone,it is preferable to present it as a pharmaceutical composition.

Accordingly, the present invention further provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and, asactive ingredient, a therapeutically effective amount of a compoundaccording to Formula (I), a pharmaceutically acceptable acid or baseaddition salt, or a solvate thereof.

The carrier or diluent must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

For ease of administration, the subject compounds may be formulated intovarious pharmaceutical forms for administration purposes. The compoundsaccording to the invention, in particular the compounds according toFormula (I), and the pharmaceutically acceptable acid or base additionsalts and the solvates thereof, or any subgroup or combination thereofmay be formulated into various pharmaceutical forms for administrationpurposes. As appropriate compositions there may be cited allcompositions usually employed for systemically administering drugs.

To prepare the pharmaceutical compositions of this invention, aneffective amount of the particular compound as the active ingredient iscombined in intimate admixture with a pharmaceutically acceptablecarrier, which carrier may take a wide variety of forms depending on theform of preparation desired for administration. These pharmaceuticalcompositions are desirable in unitary dosage form suitable, inparticular, for administration orally, rectally, percutaneously, byparenteral injection or by inhalation. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed such as, for example, water, glycols, oils, alcohols andthe like in the case of oral liquid preparations such as suspensions,syrups, elixirs, emulsions and solutions; or solid carriers such asstarches, sugars, kaolin, diluents, lubricants, binders, disintegratingagents and the like in the case of powders, pills, capsules and tablets.Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit forms in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, for example, to aid solubility,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable solutions, forexample, may be prepared in which the carrier comprises saline solution,glucose solution or a mixture of saline and glucose solution. Injectablesolutions containing a compound of Formula (I), a pharmaceuticallyacceptable acid or base addition salt, or a solvate thereof, may beformulated in an oil for prolonged action. Appropriate oils for thispurpose are, for example, peanut oil, sesame oil, cottonseed oil, cornoil, soybean oil, synthetic glycerol esters of long chain fatty acidsand mixtures of these and other oils. Injectable suspensions may also beprepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. Also included are solid form preparationsthat are intended to be converted, shortly before use, to liquid formpreparations. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notintroduce a significant deleterious effect on the skin. Said additivesmay facilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid or base addition salts of compounds ofFormula (I) due to their increased water solubility over thecorresponding base or acid form, are more suitable in the preparation ofaqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in unit dosage form for ease ofadministration and uniformity of dosage. Unit dosage form as used hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical carrier. Examples of such unit dosage forms aretablets (including scored or coated tablets), capsules, pills, powderpackets, wafers, suppositories, injectable solutions or suspensions andthe like, and segregated multiples thereof

Since the compounds according to the invention are potent orallyadministrable compounds, pharmaceutical compositions comprising saidcompounds for administration orally are especially advantageous.

In order to enhance the solubility and/or the stability of the compoundsof Formula (I), pharmaceutically acceptable acid or base addition saltsand the solvates thereof, in pharmaceutical compositions, it can beadvantageous to employ α-, β- or γ-cyclodextrins or their derivatives,in particular hydroxyalkyl substituted cyclodextrins, e.g.2-hydroxypropyl-β-cyclodextrin or sulfobutyl-β-cyclodextrin. Alsoco-solvents such as alcohols may improve the solubility and/or thestability of the compounds according to the invention in pharmaceuticalcompositions.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of Formula (I), a pharmaceutically acceptableacid or base addition salt, or a solvate thereof, and from 1 to 99.95%by weight, more preferably from 30 to 99.9% by weight, even morepreferably from 50 to 99.9% by weight of a pharmaceutically acceptablecarrier, all percentages being based on the total weight of thecomposition.

The following examples illustrate the present invention. In case nospecific stereochemistry is indicated for a stereocenter of a compound,this means that the compound was obtained as a mixture of the R and theS enantiomers.

Examples

Hereinafter, the term “NaH” means sodium hydride (60% in mineral oil);“DCM” means dichloromethane; “LiBr” means lithium bromide; “POCl₃” meansphosphorus oxychloride; “MeOH” means methanol; “sat.” means saturated;“LCMS” means Liquid Chromatography/Mass spectrometry; “HPLC” meanshigh-performance liquid chromatography; “sol.” means solution; “aq.”means aqueous; “r.t.” means room temperature; “tBu” means tert-butyl;“AcOH” means acetic acid; “TFA” means trifluoroacetic acid; “m.p.” meansmelting point; “N₂” means nitrogen; “RP” means reversed phase; “min”means minute(s); “h” means hour(s); “Na₂SO₃” means sodium sulphite;“EtOAc” means ethyl acetate; “Et₃N” means triethylamine; “EtOH” meansethanol; “eq.” means equivalent; “r.m.” means reaction mixture(s);“DIPE” means diisopropyl ether; “THF” means tetrahydrofuran; “DMF” meansN,N-dimethyl formamide; ‘iPrOH” means 2-propanol; “LDA” means lithiumdiisopropylamide; “NH₃” means ammonia; “SFC” means Supercritical FluidChromatography; “TBAF” means tetrabutylammonium fluoride; “OR” meansoptical rotation; “DIPEA” means diisopropylethylamine; “NH₄HCO₃” meansammonium bicarbonate; “NH₄OAc” means ammonium acetate; “TfOH” meanstrifluoromethanesulfonic acid; “v/v” means volume/volume %; “w/v” meansweight/volume; “Cs₂CO₃” means cesium carbonate; “DIAD” means diisopropylazodicarboxylate; “DMAP” means 4-dimethylaminopyridine; “HBTU” meansO-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate;“CO₂” means carbon dioxide; “iPrNH₂” means isopropylamine; “Na₂CO₃”means sodium carbonate; “HCl” means hydrochloric acid; “K₂CO₃” meanspotassium carbonate; “K₃PO₄” means potassium phosphate; “MgSO₄” meansmagnesium sulphate; “Na₂SO₄” means sodium sulphate; “NaBH₄” means sodiumborohydride; “LiAlH₄” means lithium aluminium hydride; “Et₂O” meansdiethyl ether; “NaHCO₃” means sodium hydrogencarbonate; “NaOH” meanssodium hydroxide; “NH₄Cl” means ammonium chloride; “Pd/C” meanspalladium on carbon; “Et” means ethyl; “Me” means methyl; “Pd₂(dba)₃”means tris(dibenzylideneacetone)dipalladium(0); “Xantphos” means4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; “H₂” means hydrogen;“TPP” means triphenylphospine; “X-Phos” means2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; “MsCl” meansmethansulphonyl chloride; “TLC” means thin layer chromatography, “DDQ”means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and “DABCO” means1,4-diazabicyclo[2.2.2]octane.

A. Preparation of the Intermediates Example A1 a) Preparation ofIntermediate 1

p-Anisaldehyde (7.4 mL, 61 mmol) was dissolved in MeOH (300 mL), thenD-alaninol (5.0 g, 66 mmol) and NaHCO₃ (10.2 g, 121 mmol) were added andthe reaction stirred at 80° C. for 2 h. The r.m. was then cooled to 25°C. NaBH₄ (2.3 g, 61 mmol) was added portionwise while keeping thetemperature below 25° C. The mixture was stirred at 25° C. for 1additional h, then quenched with 2N HCl (pH=1) and NaHCO₃ (pH=7-8). MeOHwas evaporated in vacuo, then EtOAc was added. The organic layer wasseparated, dried over MgSO₄, filtered and the solvents evaporated invacuo to yield intermediate 1 as a white solid (quantitative yield;R-enantiomer).

b) Preparation of Intermediate 2

HBTU (2.15 g, 5.67 mmol) was added to a stirred solution of6-(benzyloxy)pyridine-2-carboxylic acid (1 g, 4.36 mmol), DIPEA (1 mL,5.68 mmol) and intermediate 1 (0.85 g, 4.36 mmol) in DMF (12 mL). Themixture was stirred at r.t. overnight. Sat. aq. NaHCO₃ sol. was addedand the mixture was extracted with EtOAc. The combined extracts weredried over MgSO₄ and concentrated in vacuo. The crude product waspurified by flash column chromatography (silica; hexanes/EtOAc 100/0 to50/50). The desired fractions were collected and concentrated in vacuoto yield intermediate 2 as an oil (1.51 g, 85%; R-enantiomer).

c) Preparation of Intermediate 3

10% Pd/C (0.187 g) was added to a solution of intermediate 2 (1.87 g,4.60 mmol) in MeOH (20 mL) at 0° C. The mixture was hydrogenated(atmospheric pressure) at r.t. for 6 h. The catalyst was filteredthrough diatomaceous earth and the solvent evaporated in vacuo to yielda colorless oil. The crude intermediate 3 was used as such in the nextreaction step (quantitative yield; R-enantiomer).

d) Preparation of Intermediate 4

DIAD (1.36 mL, 6.90 mmol) was added to a stirred solution ofintermediate 3 (crude material, 4.60 mmol) and TPP (1.8 g, 6.86 mmol) indry THF (20 mL) under N₂. The mixture was stirred at r.t. overnight. Thesolvents were then evaporated in vacuo. The crude product was purifiedby flash column chromatography (silica; hexanes/EtOAc 100/0 to 0/100).The desired fractions were collected and concentrated in vacuo to affordintermediate 4 as a white solid (927 mg, 68% over two steps;R-enantiomer).

e) Preparation of Intermediate 5

Trifluoromethanesulfonic acid (30 mL) was added dropwise to a warm (50°C.), stirred solution of intermediate 4 (10.5 g, 35 mmol) in TFA (175mL) and anisole (4 g). After 2 h at this temperature the r.m. was cooledto r.t. and concentrated in vacuo. The dark purple residue was dissolvedin acetonitrile (50 mL) and added dropwise to a cooled (−60° C.) sol. of7 M NH₃ in MeOH (250 mL). The brownish supension was filtered and silicawas added to the filtrate. The mixture was concentrated in vacuo and thecrude product was purified by column chromatography (silica, DCM/7 N NH₃in MeOH 100/0 to 96/4), to give a brown solid, which was used withoutfurther purification in the subsequent reaction (4 g, R-enantiomer).

f) Preparation of Intermediate 6

Lithium hydroxide monohydrate (0.766 g, 18.25 mmol) was addedportionwise to a stirred solution of methyl3-bromo-2-hydroxy-6-pyridinecarboxylate (3.85 g, 16.6 mmol) in a mixtureof THF (66 mL) and water (17 mL). The mixture was stirred at 60° C. for24 h and then the solvent was evaporated in vacuo. The crudeintermediate 6 was dried in vacuo and used as such in the next reactionstep (quantitative yield; R-enantiomer).

g) Preparation of Intermediate 7

Bromine (0.17 mL, 3.32 mmol) was added dropwise slowly to a stirredsolution of intermediate 11 (0.825 g, 2.76 mmol) in DCM/AcOH 4:1 (15 mL)under N₂. The mixture was stirred at r.t. overnight, then diluted withaq. sat. NaHCO₃ sol. and extracted with DCM. The organic layer wasseparated, dried over MgSO₄, filtered and the solvents evaporated invacuo. The crude product was purified by flash column chromatography(silica; hexanes/EtOAc 100/0 to 50/50). The desired fractions werecollected and concentrated in vacuo to yield intermediate 7 as an oil(530 mg, 51%; R-enantiomer).

g1) Alternative Preparation of Intermediate 7

HBTU (16.2 g, 42.66 mmol) was added portionwise to a stirred solution ofintermediate 6 (crude material, 28.44 mmol), intermediate 1 (5.55 g,28.44 mmol) and DIPEA (7.3 mL, 42 mmol) in DMF (24 mL). The mixture wasstirred at r.t. for 14 h, then 0.5 additional eq. of HBTU and DIPEA wereadded. The mixture was stirred at r.t. for 4 h, then poured into aq.sat. NaHCO₃ sol. and extracted with EtOAc. The organic layer wasseparated, dried over MgSO₄, filtered and the solvents evaporated invacuo. The crude product was purified by flash column chromatography(silica; EtOAc/heptanes 0/100 to 50/50). The desired fractions werecollected and concentrated in vacuo to yield intermediate 7 as an oil(7.03 g, 65% over two steps; R-enantiomer).

h) Preparation of Intermediate 8

Trifluoromethanesulfonic acid (0.5 mL, 5.62 mmol) was added to a stirredsolution of intermediate 7 (0.53 g, 1.4 mmol) in toluene (5 mL). Themixture was stirred at reflux for 2 h, then diluted with 1M NaOH to pH=8and the solvents evaporated in vacuo. The crude product was purified byflash column chromatography (silica; DCM/EtOAc 100/0 to 0/100). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate 8 as a solid (0.297 g, quantitative yield, R-enantiomer).

h1) Alternative Preparation of Intermediate 8

To a stirred and ice-cooled mixture of intermediate 5 (4 g, 22.4 mmol)in DCM (50 mL) and AcOH (10 mL) was added dropwise bromine (1.6 mL, 31.4mmol) in DCM (2.5 mL). After stirring for 4 h at r.t. the r.m. wasdiluted with DCM (200 mL) and successively treated with 20% Na₂SO₃ sol.until a colorless r.m. was obtained, and then with saturated aq. NaHCO₃sol. until pH neutral. The layers were separated and the organic layerwas dried over MgSO₄, filtered and concentrated in vacuo to afford anoff white solid (4.5 g), which was used without further purification inthe subsequent reaction.

Example A2 a) Preparation of Intermediate 9

N-Benzylethanolamine (26.3 mL, 182.84 mmol) was added to a mixture ofmethyl 2-hydroxy-6-pyridinecarboxylate (14 g, 91.42 mmol) and MeOH (92mL). The r.m. was stirred under reflux until completion of the reaction.Then the solvent was evaporated and the crude product purified by flashcolumn chromatography (silica; DCM/MeOH 100/0 to 90/10). The desiredfractions were collected and concentrated in vacuo to affordintermediate 9 (23.2 g, 93%).

b) Preparation of Intermediate 10

DIAD (19.0 mL, 96.12 mmol) was added to a stirred solution ofintermediate 9 (17.45 g, 64.08 mmol) and TPP (25.21 g, 96.12 mmol) indry THF (193 mL) under N₂. The mixture was stirred at r.t. for 2 h. Thesolvents evaporated in vacuo. The crude product was purified by flashcolumn chromatography (silica; DCM/EtOAc 100/0 to 0/100). The desiredfractions were collected and concentrated in vacuo to give intermediate10 as a white solid (16.294 g, quantitative yield).

c) Preparation of Intermediate 11

Bromine (0.67 mL, 12.96 mmol) was added dropwise slowly to a stirredsolution of intermediate 10 (2.75 g, 10.8 mmol) in DCM/AcOH 4:1 (50 mL)under N₂. The mixture was stirred at r.t. overnight, then diluted withaq. sat. NaHCO₃ sol. and extracted with DCM. The organic layer wasseparated, dried over MgSO₄, filtered and the solvents were evaporatedin vacuo. The crude product was purified by flash column chromatography(silica; DCM/EtOAc 100/0 to 80/20). The desired fractions were collectedand concentrated in vacuo to yield intermediate 11 as a yellow solid(quantitative yield).

d) Preparation of Intermediate 12

Trifluoromethanesulfonic acid (5.05 g, 15.15 mmol) was added to astirred solution of intermediate 11 (5.4 mL, 60.6 mmol) in dry toluene(50 mL). The mixture was stirred at reflux for 24 h, then diluted withsat. NH₃ and the solvents were evaporated in vacuo. The crude productwas purified by flash column chromatography (silica; DCM/MeOH 100/0 to94/6). The desired fractions were collected and concentrated in vacuo toyield intermediate 12 as a white solid (quantitative yield).

Example A3 a) Preparation of Intermediate 13

K₃PO₄ (0.731 g, 3.44 mmol), Pd₂(dba)₃ (63 mg, 0.06 mmol) and Xantphos(69 mg, 0.12 mmol) were added to a stirred solution of intermediate 7(0.65 g, 1.72 mmol) in dry THF (5 mL) at r.t., while N₂ was bubbledthrough the mixture. After 10 min, acetamide (0.112 g, 1.89 mmol) wasadded and the mixture was stirred for another 10 min, then stirred for 3h at 90° C. in a closed vessel. The reaction was then cooled to r.t. andsat. NaHCO₃ sol. and EtOAc were added. The phases were separated, theaqueous phase extracted once more with EtOAc, the combined organics weredried over MgSO₄, filtered and evaporated. The crude was purified byflash column chromatography (silica; hexanes/EtOAc 100/0 to 10/90). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate 13 as a pale yellow foam (0.335 g, 56%; R-enantiomer).

b) Preparation of Intermediate 14

HCl (6N in 2-propanol, 0.5 mL, 2.82 mmol) was added to a solution ofintermediate 13 (0.335 g, 0.94 mmol) in MeOH (5 mL) at r.t. and themixture was stirred overnight. The solvent was then evaporated, sat.NaHCO₃ sol. and EtOAc were added, the phases were separated, the aqueousphase was extracted once more and the combined organics were dried overMgSO₄, filtered and evaporated. The crude intermediate 14 was used assuch in the next reaction step, and the yield considered to bequantitative (R-enantiomer).

c) Preparation of Intermediate 15

Acetic anhydride (0.34 mL, 3.58 mmol) was added dropwise to formic acid(0.5 mL, 14.13 mmol) at r.t. and stirred for 30 min at the sametemperature. To this solution was added dropwise intermediate 14 (crudematerial, 0.94 mmol) in THF (6 mL). The r.m. was stirred 16 h at 60° C.,then water and EtOAc were added. The phases were separated and theaqueous phase was extracted once more. The combined organics were driedover MgSO₄, filtered and evaporated. The crude intermediate 15 was usedas such in the next reaction step, and the yield considered to bequantitative (R-enantiomer).

d) Preparation of Intermediate 16

Chloroacetone (0.19 mL, 2.35 mmol) was added dropwise to a stirredsuspension of intermediate 15 (crude material, 0.94 mmol), K₂CO₃ (0.456g, 3.29 mmol) and potassium iodide (16 mg, 0.09 mmol) in DMF (3 mL) atr.t. The mixture was stirred for 16 h, then water and EtOAc were added.The phases were separated and the aq. phase was extracted once more. Thecombined organics were dried over MgSO₄, filtered and evaporated. Thecrude intermediate 16 was used as such to the next reaction step, andthe yield considered to be quantitative (R-enantiomer).

e) Preparation of Intermediate 17

NH₄OAc (0.362 g, 4.70 mmol) was added to a stirred solution ofintermediate 16 (crude material, 0.94 mmol) in AcOH (2 mL) at r.t. andthe mixture was stirred for 1 h at reflux. The reaction was then cooledto r.t. and poured into water at 0° C. Aq. 50% NaOH sol. was addedslowly until basic pH. The product was extracted with EtOAc (×2). Thecombined organics were dried over MgSO₄, filtered and evaporated. Thecrude was purified by flash column chromatography (silica; DCM/MeOH100/0 to 90/10). The desired fractions were collected and concentratedin vacuo to yield intermediate 17 as a sticky brown oil (0.2 g, 57% over4 steps; R-enantiomer).

f) Preparation of Intermediate 18

TfOH (0.2 mL, 2.11 mmol) was added to a stirred solution of intermediate17 (0.2 g, 0.52 mmol) in dry toluene (2.5 mL) at r.t. and the mixturewas stirred for 2 h at reflux. The solvent was then evaporated. Aq. 1NNaOH sol. was added until pH 8 and the solvents were evaporated. Thecrude was triturated with DCM-MeOH (9:1, v/v), dried over MgSO₄,filtered and evaporated. The crude intermediate 18 was used as such inthe next reaction step, and the yield considered to be quantitative(R-enantiomer).

f1) Alternative Preparation of Intermediate 18

In a first vial equipped with a magnetic stir bar and a screw capseptum, a solution of Pd₂(dba)₃ (0.055 g, 0.06 mmol) and2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl(0.06 g, 0.125 mmol) in dioxane (1.5 mL) and toluene (7 mL) was flushedwith N₂ and then stirred at 120° C. for 3 min. A second vial, equippedwith a magnetic stir bar and a screw cap septum, was charged with4-methylimidazole (0.45 g, 5.5 mmol) and K₃PO₄ (2.12 g, 10 mmol), thenwith intermediate 8 (1.312 g, 5 mmol) and also flushed with N₂. Thepremixed catalyst solution was added by syringe to the second vial. Ther.m. was heated at 120° C. for 5 h. The reaction was cooled to r.t,diluted with DCM, washed with brine and neutralized with NH₄Cl. Thesolvents were evaporated until dryness. The crude was purified by columnchromatography (silica; DCM/MeOH 95/5 to 80/20). The fractions werecollected to give intermediate 18 (1.33 g, 98%; R-enantiomer).

Example A4 a) Preparation of Intermediate 19

Thionyl chloride (0.4 mL, 4.86 mmol) was added to a solution of6-(benzyloxy)-pyridine-2-carboxylic acid (0.724 g, 3.24 mmol) and a dropof DMF in DCM (15 mL). The mixture was stirred at r.t. for 2 h, then thesolvent was removed under reduced pressure and the crude intermediate 19used as such in the next reaction step, and the yield considered to bequantitative.

Example A5 a) Preparation of Intermediate 20

Intermediate 20 was obtained by following a synthetic procedure similarto the one reported for the synthesis of intermediate 18.

Example A6 a) Preparation of Intermediate 21

NaH (4.78 g, 119.61 mmol) was added to a stirred solution of benzylalcohol (13.6 mL, 131.57 mmol) in dry THF (50 mL) at 0° C. After 30 min,this mixture was added to a stirred solution of2-bromo-1-iodo-3,5-bis(trifluoromethyl)benzene (19.27 g, 23.92 mmol) indry THF (80 mL). The mixture was stirred at r.t. overnight, thenquenched with water and extracted with heptanes. The combined organicswere dried over MgSO₄, filtered and concentrated in vacuo. The crudematerial was purified by flash column chromatography (silica; hexane).The desired fractions were collected and concentrated in vacuo to yieldintermediate 21 (7.83 g, 73%).

b) Preparation of Intermediate 22

Buthyl lithium (2.5 M in hexane, 3.2 mL, 8.07 mmol) was added dropwiseto a stirred solution of intermediate 21 (3 g, 6.72 mmol) in dry THF (20mL) at −78° C. The mixture was stirred for 1 h at the same temperature,then t-butyldimethylsiloxyacetaldehyde (1.4 mL, 7.40 mmol) was addeddropwise. The r.m. was stirred for 2 h, then quenched with sat. aq.NH₄Cl sol. and extracted with EtOAc. The combined organics were driedover MgSO₄, filtered and evaporated. The crude material was purified byflash column chromatography (silica; heptanes/DCM 0/100 to 50/50). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate 22 as a yellow oil (1.20 g, 36%, mixture of R and Senantiomers).

c) Preparation of Intermediate 23

MsCl (0.23 mL, 2.91 mmol) was added dropwise to a stirred solution ofintermediate 22 (1.2 g, 2.43 mmol) and DIPEA (0.7 mL, 4.12 mmol) in DCM(25 mL) at 0° C. The mixture was stirred overnight at r.t., then dilutedwith DCM and washed with sat. aq. NaHCO₃ sol. The organic phase wasdried over MgSO₄, filtered and concentrated in vacuo. The crude materialwas used as such for the subsequent reaction step (1.389 g, quantitativeyield; mixture of R and S enantiomers).

d) Preparation of Intermediate 24

NaH (0.084 mg, 2.10 mmol) was added to a stirred solution ofintermediate 18 (0.418 g, 1.62 mmol) and LiBr (0.168 mg, 1.94 mmol) inDMF (15 mL) at 0° C. under N₂ atmosphere. The mixture was stirred for 15min and then intermediate 23 (1.389 g, crude material) was addeddropwise. The r.m. was stirred overnight at r.t. and then 2 h at 50° C.The reaction was quenched with water and extracted with EtOAc. Theorganic phase was dried over MgSO₄, filtered and concentrated in vacuo.The crude was purified by flash column chromatography (silica; DCM/MeOH100/0 to 90/10). The desired fractions were collected and concentratedin vacuo to afford intermediate 24 (96 mg, 8%; R,RS).

e) Preparation of Intermediate 25

Boron tribromide (0.055 mL, 0.57 mmol) was added portionwise to astirred solution of intermediate 24 (0.097 mg, 0.132 mmol) in DCM (10mL) at 0° C. under N₂. The mixture was stirred at r.t. for 1 h, thendiluted with aq. sat. NaHCO₃ and extracted with DCM. The organic layerwas separated, dried over MgSO₄, filtered and the solvents evaporated invacuo. The crude material was used as such for the subsequent reactionstep (70 mg, quantitative yield; R,RS).

Example A7 a) Preparation of Intermediate 26

2-Hydrazinyl-5-trifluoromethylpyridine (9.5 g, 53.63 mmol) was stirredin pyridine (261 mL) and DMF (261 mL). Methyl oxalyl chloride (7.885 g,64.36 mmol) was added at 0° C. The r.m. was stirred for 1 h, then thesolvents evaporated and the residue dissolved in DCM/water. The productprecipitated and was filtered off and dried, to afford intermediate 26(9.78 g, 69%).

b) Preparation of Intermediate 27

Intermediate 26 (9.78 g, 37.16 mmol) was stirred in POCl₃ (73 mL) andthe r.m. was refluxed for 20 h, then allowed to cool down. Ice-water wasadded carefully at 0° C., then DCM was added until 2 layers were formedwithout any remaining solids. The mixture was basified with solidNaHCO₃. The organic layer was separated, dried over MgSO4, filtered andthe solvents evaporated in vacuo. The product was purified by flashcolumn chromatography (silica; DCM/MeOH 100/0 to 99/1). The desiredfractions were collected and concentrated in vacuo to affordintermediate 27 (2.03 g, 22%).

c) Preparation of Intermediate 28

10% Pd/C (0.43 g), was added to intermediate 27 (1 g, 4.08 mmol) andMeOH (50 mL). The mixture was hydrogenated (20 bar H₂) at 50° C. for 20h. The catalyst was filtered off and the solvent evaporated in vacuo toyield intermediate 28 (1.05 g, used as such in the next step).

d) Preparation of Intermediate 29

Intermediate 28 (1.05 g, crude material) was stirred in THF (50 mL) andMeOH (50 mL) at r.t. under N₂. NaBH₄ (0.228 g, 6.02 mmol) was added andthe mixture was stirred overnight at r.t., then sat. aq. NH₄Cl sol. wasadded and the solvent evaporated. DCM was added, the mixture dried overMgSO₄, filtered and the solvent evaporated in vacuo, to yieldintermediate 29 (0.36 g).

e) Preparation of Intermediate 30

Intermediate 29 (0.36 g) was stirred in DCM (9 mL) at 0° C. under N₂atmosphere. Thionyl chloride (0.387 g, 3.26 mmol) was added and themixture was allowed to reach r.t. After TLC control, the mixture wasevaporated and co-evaporated with toluene and used as such in the nextstep (0.39 g).

Example A8 a) Preparation of Intermediate 31

To 4-trifluoromethylpyridine (4.37 g, 29.73 mmol) in DCM (30 mL) at 0°C. was added o-mesitylenesulfonylhydroxylamine (6.40 g, 29.73 mmol) insmall portions. The r.m. was stirred at 0° C. for 1 h, then at r.t. for20 h. Heptane was then added. An oily solid was formed, which wasfiltered. After filtration, the collected white solid was dissolved inDMF (50 mL), then K₂CO₃ (6.16 g, 44.60 mmol) and methyl propiolate (2.50g, 29.73 mmol) were added. The r.m. was stirred for 20 h at r.t., thenfiltered and the solvent evaporated in vacuo. The residue was treatedwith DCM/sat. aq. NaHCO₃ sol. The organic layer was separated, washedwith 1N HCl sol., dried over MgSO₄, filtered and evaporated. The crudewas purified by flash column chromatography (silica, heptanes/EtOAc100/0 to 98/2) to afford intermediate 31 as a white solid (2 g, 28%).

b) Preparation of Intermediate 32

By following a procedure similar to the one reported for the synthesisof intermediate 28, starting from intermediate 31 intermediate 32 wasobtained and used as a crude for the subsequent synthetic step.

c) Preparation of Intermediate 33

Intermediate 32 (1.4 g, crude material) was dissolved in THF (0.5 mL)under N₂ atmosphere. LiAlH₄ (1 M in THF, 5.6 mL, 5.64 mmol) was added atr.t. and the r.m. was stirred for 1 h. The r.m. was then cooled andwater was carefully added (10 mL). The solvents were evaporated in vacuoand the residue treated with DCM. MeOH and water. The organic layer wasseparated, dried over MgSO₄, filtered and evaporated, to yieldintermediate 33 (0.9 g).

d) Preparation of Intermediate 34

By following a procedure similar to the one reported for the synthesisof intermediate 30, starting from intermediate 33 intermediate 34 wasobtained and used as a crude for the subsequent synthetic step.

Example A9 a) Preparation of Intermediate 35

2-Hydrazinyl-5-trifluoromethylpyridine (5 g, 28.23 mmol) was stirred indry THF (50 mL) and Et₃N (2.856 g, 28.23 mmol). Chloroacetyl chloride(3.188 g, 28.23 mmol) was added at 0° C. The r.m. was stirred at 0° C.for 3 h, then ice-water was added and the mixture extracted with DCM.The organic layer was washed with water, dried over MgSO₄, filtered andthe solvent evaporated to afford intermediate 35 (6.16 g, 86%).

b) Preparation of Intermediate 36

Intermediate 35 (3 g, 11.83 mmol) and POCl₃ (30 mL) were refluxed for 20h, then the POCl₃ was evaporated and the residue was stirred inice-water. The water layer was brought to pH=6 and the product wasextracted with DCM. The organic layer was dried over MgSO₄, filtered andevaporated. The product was purified by flash column chromatography(silica; DCM/acetonitrile 98/2 to 90/10). The pure fractions werecollected and the solvent was removed in vacuo at 35° C., yieldingintermediate 36 (1 g, 36%).

Example A10

Following a procedure similar to the one described for the synthesis ofintermediate 30, following intermediates were prepared starting from thecommercially available or known corresponding alcohols:

Structure Intermediate number

37

38

Example A11 a) Preparation of Intermediate 39

6-Bromo-chroman-2-carboxylic acid methyl ester (3.5 g, 12.91 mmol) wasdissolved in THF (88 mL) under N₂ atmosphere, then the solution wascooled to −72° C. LDA (2 M in THF, 8 mL, 16.14 mmol) was added dropwise,and the r.m. stirred at −70° C. for 1.5 h. Methyl iodide (8 mL, 129.1mmol) in THF (5 mL) was then added dropwise, and the reaction mixturestirred for 20 h while reaching room temperature. After this time MeOH(10 mL) was added, followed by EtOAc and water. The organic layer wasseparated, filtered, dried over MgSO₄ and the solvent removed in vacuo.The crude was purified by flash column chromatography (silica;heptanes/EtOAc 100/0 to 98/2). The desired fractions were collected andthe solvent evaporated to afford intermediate 39 (1.6 g, 43%).

b) Preparation of Intermediate 40

Intermediate 39 (1.6 g, 5.61 mmol) was dissolved in THF (0.5 mL) underN₂ atmosphere. Lithium borohydride (2 M in THF, 8.4 mL, 16 mmol) wasadded dropwise at r.t. and the r.m. stirred for 1 h. Extra lithiumborohydride (4 mL) was added and the r.m. stirred for 1 h at r.t., thenMeOH was added and the mixture allowed to stir for 5 min. After thistime the volatiles were removed in vacuo and the residue was dissolvedin DCM/water. The organic layer was separated, dried over MgSO₄,filtered and the solvent evaporated. Purification by flash columnchromatography (silica; heptanes/EtOAc 100/0 to 98/2) affordedintermediate 40.

c) Preparation of Intermediate 41

To a solution of intermediate 40 (0.7 g, 2.72 mmol) in pyridine (20 mL)at 0° C. was added p-toluenesulfonyl chloride (0.571 g, 3 mmol). Thereaction mixture was stirred at r.t. overnight, then the solvent wasremoved in vacuo. Aq. NaHCO₃ sol. was added and the product wasextracted with DIPE. The organic layer was dried on MgSO₄, filtered andevaporated. The product was purified by flash column chromatography(silica; DCM/MeOH from 100/0 to 99/1). The fractions containing thedesired product were evaporated, to afford intermediate 41 (0.5 g, 45%).

Example A12 a) Preparation of Intermediates 42 and 43

NaH (1.23 g, 31.15 mmol) was dissolved in DMF (200 mL) under N₂atmosphere at 0° C. To this solution was added ethyl5-isopropylpyrazole-3-carboxylate (5.16 g, 28.33 mmol) in DMF (50 mL)over 10 min at 0° C. After the addition, the r.m. was stirred for 10 minat 0° C. and then at r.t. for 40 min. 2,2,2-Trifluoroethyltrifluoromethanesulfonate (4.5 mL, 31.15 mmol) was subsequently addedand the mixture was stirred at r.t. for 3 h. After this time the rm wasquenched by addition of EtOH at 0° C. Water was added to the mixture andthe water layer was extracted with EtOAc. The organic layer was thenwashed with brine, dried (MgSO4), filtered and concentrated in vacuo.The resulting crude was purified by flash column chromatography (silica;heptanes/EtOAc 100/0 to 60/40) to afford intermediate 42 (4.05 g, 54%)and regioisomer intermediate 43 (1.52 g, 20%).

b) Preparation of Intermediate 44

By following a procedure similar to the one reported for the synthesisof intermediate 33, starting from intermediate 42 intermediate 44 wasobtained (68%).

c) Preparation of Intermediate 45

Intermediate 44 (0.86 mg, 3.87 mmol) was dissolved in DCM (25 mL). Thesolution was cooled down to 0° C. MsCl (0.33 mL, 4.26 mmol) and Et₃N(0.6 mL, 4.26 mmol) were added and the r.m. was stirred at r.t. untilcompletion. Water was then added and the organic layer washed with aq.sat. Na₂CO₃ sol., dried over Na₂SO₄, filtered and concentrated in vacuoto give a crude, which was used in the subsequent step without furtherpurification.

Example A13 a) Preparation of Intermediate 46

Butyl lithium (1.6 M in hexane, 2.6 mL, 4.18 mmol) was added dropwise toa solution of 2-methyl-5-(trifluoromethyl)bromobenzene (1 g, 4.18 mmol)in Et₂O (15 mL) at −78° C. The r.m. was stirred at −78° C. for 20 minand then 1-(tert-butyldimethylsilyloxy)-2-propanone (0.827 g, 4.39 mmol)in Et₂O (5 mL) was added and the r.m. was further stirred for 2 h at−78° C. The r.m. was then quenched with water and the product wasextracted with EtOAc. The organic layer was dried over MgSO₄, filteredand the solvent was removed in vacuo. The crude product was purified byflash column chromatography (silica; heptanes/EtOAc 100/0 to 90/10). Thefractions containing the product were collected and concentrated invacuo to give intermediate 46 (1.036 g, 71%).

b) Preparation of Intermediate 47

Intermediate 46 (4.84 g, 13.89 mmol) was stirred in carbon tetrachloride(194 mL). N-bromosuccinimide (2.719 g, 15.28 mmol) and2,2′-azobis(2-methylpropionitrile) (0.228 g, 1.39 mmol) were added andthe mixture was refluxed for 2 h. The reaction mixture was then washedwith 1N NaOH sol., dried over MgSO₄, filtered and evaporated, yieldingintermediate 47, which was used as such in the subsequent reaction step,and the yield considered to be quantitative (4.8 g).

c) Preparation of Intermediate 48

Intermediate 47 (4.8 g, crude material) and a solution of TBAF in THF(40 mL; 1 M) were stirred at r.t. for 2 h. Sat. NH₄Cl sol. was added andthe product was extracted with EtOAc. The organic layer was washed withwater (×2) and once with brine, dried over MgSO₄, filtered andevaporated, yielding intermediate 48. The crude material was used assuch for the subsequent reaction step, and the yield considered to bequantitative (3.2 g).

d) Preparation of Intermediate 49

By following a procedure similar to the one reported for the synthesisof intermediate 41, starting from intermediate 48 intermediate 49 wasobtained.

Example A14 a) Preparation of Intermediate 50

By following a procedure similar to the one reported for the synthesisof intermediate 45, starting from intermediate 43 intermediate 50 wasobtained.

Example A15 a) Preparation of Intermediates 51 and 52

1,2-Benzisothiazole-3-carboxylic acid (4 g, 22.32 mmol) was dissolved inAcOH (64 mL). Nitric acid (19 mL) and sulfuric acid (3.8 mL) were added,followed by bromine (1.7 mL, 33.48 mmol). The reaction mixture wasstirred overnight at 70° C., then allowed to reach r.t. The residue waspoured into ice-water and the precipitate filtered off. The crudematerial was used as such for the subsequent step (7.5 g, mixture ofintermediates 51 and 52 in a ratio of 17:7 by LC-MS).

b) Preparation of Intermediates 53 and 54

The crude mixture of intermediate 51 and intermediate 52 (5.7 g) wasdissolved in MeOH (300 mL). Sulfuric acid (10 mL) was added and the r.m.stirred at 60° C. for 3 h. The solvent was evaporated in vacuo, DCM wasadded and the mixture cooled with an ice bath. NaHCO₃ sat. sol. wasadded carefully until pH ˜8. The organic layer was separated, dried overMgSO₄, filtered and the solvent was evaporated in vacuo to afford amixture of intermediates 53 and 54 in a ratio of 21:11 by LC-MS, whichwas used as such for the subsequent step (4.4 g).

c) Preparation of Intermediates 55 and 56

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 40 and intermediate 45, starting fromintermediates 53 and 54 intermediates 55 and 56 were obtained.

Example A16 a) Preparation of Intermediate 57

Et₃N (1.2 mL, 8.87 mmol) and 3-aminobenzotrifluoride (1 mL, 8.07 mmol)in THF (10 mL) were added to 2,4-dibromobutyryl chloride (1.2 mL 9.41mmol) in THF (10 mL) at 5° C. The r.m. was stirred at r.t. over theweekend, then sat. aq. NH₄Cl sol. was added and the r.m. extracted withEtOAc (×3). The combined organic layers were washed with water (×2) andbrine, then dried over MgSO₄, filtered and evaporated to give the crudeproduct as a brown solid, which was used without further purification inthe subsequent step (2.92 g).

b) Preparation of Intermediate 58

NaH (0.39 g, 9.75 mmol) was added portionwise to intermediate 57 (2.92g, crude material) in THF (60 mL) at r.t. The r.m. was stirred at r.t.for 1 h, then additional NaH (0.075 g, 1.88 mmol) were added. The r.m.was stirred for 1 h, until completion. Water was carefully added, thenthe mixture extracted with EtOAc (×3). The combined organic layers werewashed with brine, dried over MgSO₄ and the solvent was evaporated invacuo to give an orange oily solid, which was purified by trituration inDIPE, to give intermediate 58 as a white solid (0.64 mg, 28%).

Example A17 a) Preparation of Intermediates 59 and 60

5-Chloro-3-indazolecarboxylic acid (1.34 g, 6.82 mmol) was dissolved indry DMF (50 mL), then the r.m. was cooled to 0° C. under N₂ atmosphere.NaH (0.6 g, 15 mmol) was added in portions, and the r.m. stirred for 20min at 0° C. Methyl iodide (0.9 mL, 15 mmol) was added dropwise, and ther.m. allowed to reach r.t. and stirred for 4 h. After this time thereaction was quenched with water, adjusted to pH=6 with 1N HCl sol. DCMwas added and the organic layer was separated and dried over MgSO₄,filtered and the solvent was evaporated. The crude material showed to bea mixture of intermediate 59 and intermediate 60 (800 mg; LC-MS ratioester/acid: 34/53), and was subsequently dissolved in MeOH (60 mL).Sulfuric acid (3 mL) was added, and the r.m. was heated at 60° C. for 4h. The solvent was then evaporated. DCM was added and the reactionmixture was basified with sat.NaHCO₃ sol. The organic layer wasseparated and dried over MgSO₄, filtered and the solvent evaporatedunder reduced pressure, to afford intermediate 59 (0.4 g, 26% over twosteps).

b) Preparation of Intermediate 61

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 34, intermediate 61 was obtained starting fromintermediate 59.

Example A18 a) Preparation of Intermediates 62 and 63

By following a synthetic procedure similar to the one reported for thesynthesis of intermediates 42 and 43, intermediate 62 and intermediate63 were obtained starting from ethyl 3-methylpyrazole-5-carboxylate.Intermediate 62 was obtained in 39% yield and intermediate 63 in 36%yield.

b) Preparation of Intermediate 64

Diisobutylaluminum hydride (1.5 M in toluene, 68 mL, 102.12 mmol) wasslowly added to intermediate 62 (8.04 g, 34.04 mmol) in DCM (161 mL) at−78° C. under N₂ atmosphere. After 2 h the reaction was quenched withMeOH and allowed to warm up to r.t., then it was diluted with DCM andtreated with an aq. sol. of Rochelle's salt (10%), and the suspensionleft to stir vigorously for 20 min. The two layers were separated, andthe organic layer dried over MgSO₄, filtered and evaporated, to giveintermediate 64 (4.98 g, 73%).

c) Preparation of Intermediate 65

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 45, intermediate 65 was obtained starting fromintermediate 64.

Example A19 a) Preparation of Intermediate 66

Phosphorus tribromide (0.12 mL, 1.22 mmol) was added to a stirredsolution of 5-trifluoromethyl-2-benzofuranmethanol (0.24 g, 1.11 mmol)in DCM (5 mL) at 0° C. The mixture was stirred at 0° C. for 90 min, thenit was neutralized with sat. aq. NaHCO₃ sol. and extracted with DCM. Theorganic layer was separated, washed with brine, dried over MgSO₄,filtered and the solvent evaporated in vacuo. The crude was purified byflash column chromatography (silica; heptane/EtOAc 100/0 to 75/25) toafford intermediate 66 (106 mg, 34%).

Example A20 a) Preparation of Intermediate 67

A solution of ethyl 2-bromothiazole-4-carboxylate (1 g, 4.24 mmol),3-(trifluoromethyl)piperidine (0.778 g, 5.08 mmol) and K₂CO₃ (1.463 g,10.59 mmol) in dimethylacetamide (36 mL) was heated at 160° C. for 6 h,then the solvent was evaporated and the residue was dissolved in EtOAcand washed with water and brine. The organic layer was dried over MgSO₄,filtered and concentrated to give a crude product, which was purified byflash column chromatography (silica; heptane/EtOAc 100/0 to 50/50) togive intermediate 67 (0.622 g, 48%).

b) Preparation of Intermediate 68

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 33 and intermediate 66, intermediate 68 wasobtained starting from intermediate 67.

Example A21 a) Preparation of Intermediate 69

To a mixture of (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (0.264 g,0.40 mmol) and pinacolborane (4.8 mL, 32.82 mmol) was added4,4′-di-tert-butyl-2,2′-dipyridyl (218 mg, 0.81 mmol) in hexane (10 mL).N₂ was bubbled through the solvent for 5 min, then a solution of methyl3-thiophenecarboxylate (3.5 g, 24.62 mmol) in hexane (2 mL) was added.The resulting red solution was stirred for 6 h at 22° C. The solvent wasthen evaporated and the residue purified by flash column chromatography(silica, heptanes/EtOAc 100/0 to 98/2) to afford impure intermediate 69(6.09 g), which was used without further purification for the subsequentreaction.

b) Preparation of Intermediate 70

A flask was charged with 3 Å molecular sieves, cesium fluoride (2.606 g,17.16 mmol), 1,10-phenanthroline (1.7 g, 9.44 mmol), and copper(II)acetate (1.575 g, 8.58 mmol) under N₂ and evacuated and backfilled withoxygen. Intermediate 69 (2.3 g) in isobutyronitrile (40 mL) and(trifluoromethyl)trimethylsilane (3.2 mL, 21.44 mmol) were added to thereaction mixture, then a balloon filled with oxygen was placed. After 90min the mixture was dissolved in EtOAc and washed with water (×3). Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuoto give a crude, which was purified by flash column chromatography(silica; heptane/EtOAc 100/0 to 70/30) to afford intermediate 70 (1 g,55%).

c) Preparation of Intermediate 71

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 68, intermediate 71 was obtained starting fromintermediate 70.

Example A22 a) Preparation of Intermediate 72

Pd₂(dba)₃ (0.116 g, 0.11 mmol), Xantphos (0.220 g, 0.38 mmol) and Cs₂CO₃(7.29 g, 22.38 mmol) were added in a tube under N₂, then dioxane (12 mL)was added. Intermediate 69 (1.5 g) and 2-iodo-1,1,1-trifluoroethane (1.1mL, 1.19 mmol) were then dissolved in dioxane (24 mL) and added to themixture. The r.m. was stirred for 1 min at r.t., then water (1.5 mL) wasadded and the mixture was stirred for 6 h at 80° C. The r.m. was pouredinto a EtOAc/water mixture and the two layers were separated. The aq.layer was extracted with EtOAc, then the organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated. Purification by flashcolumn chromatography (silica; heptanes/EtOAc 100/0 to 98/2) affordedintermediate 72 (0.584 g, 47%).

b) Preparation of Intermediate 73

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 68, intermediate 73 was obtained starting fromintermediate 72.

Example A23 a) Preparation of Intermediate 74

3-Azabicyclo[3.1.0]hexane hydrochloride (0.246 g, 2.06 mmol) was addedto a stirred solution of methyl 3-bromo-4-methylbenzoate (0.394 g, 1.72mmol), X-Phos (0.072 g, 0.15 mmol), Pd₂(dba)₃ (0.064 g, 0.07 mmol) andCs₂CO₃ (1.681 g, 5.16 mmol) in toluene (5 mL) while N₂ was bubbledthrough the r.m. The mixture was then stirred overnight at 100° C. in asealed tube. Water and EtOAc were subsequently added. The aqueous phasewas extracted once more with EtOAc and the combined organic layers weredried over MgSO₄, filtered and evaporated. The crude was purified byflash column chromatography (silica; heptanes/EtOAc 100/0 to 95/5). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate 74 as a sticky yellow oil (0.362 g, 93%).

b) Preparation of Intermediate 75

1N NaOH sol. (2.4 mL, 2.35 mmol) was added to a stirred solution ofintermediate 74 (0.362 g, 1.56 mmol) in MeOH (5 mL) at r.t. The mixturewas stirred overnight. After this time aq. 1N HCl sol. was added untilpH=4. The solvents were evaporated in vacuo and the crude was used assuch for the subsequent reaction step, and the yield considered to bequantitative (0.34 g).

c) Preparation of Intermediate 76

Borane dimethyl sulfide complex (2 M in THF, 1.9 mL, 3.91 mmol) wasadded dropwise to a stirred solution of intermediate 75 (0.34 g, crudematerial) in THF (5 mL) at 0° C. under N₂ atmosphere. The mixture wasstirred overnight at 60° C., then the reaction was cooled to r.t. Na₂CO₃was added portionwise at 0° C. The product was extracted with EtOAc(×2). The combined organic layers were dried over MgSO₄, filtered andevaporated. The crude was purified by flash column chromatography(silica; heptanes/EtOAc 100/0 to 80/20). The desired fractions werecollected and concentrated in vacuo to yield intermediate 76 as a stickypale brown oil (0.25 g, 83% over two steps).

d) Preparation of Intermediate 77

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 45, intermediate 77 was obtained starting fromintermediate 76.

Example A24

Following a procedure similar to the one described for the synthesis ofintermediate 45, following intermediate was prepared starting from theknown corresponding alcohol.

Structure Intermediate number

78

Example A25 a) Preparation of Intermediate 79

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 76 and intermediate 30, intermediate 79 wasobtained starting from commercially available3-cyclopropoxy-5-(trifluoromethyebenzoic acid.

Example A26 a) Preparation of Intermediate 80

Butyl lithium (2.5 M in hexane, 2.7 mL, 6.62 mmol) was added dropwise at−78° C. to diisopropylamine (1.0 mL, 7.22 mmol) in THF (26 mL), over 20min, and the resulting mixture was stirred for 1 h at this temperature.4-(Trifluoromethyl)cyclohexanone (1 g, 6.02 mmol) in THF (5 mL) wasadded dropwise and the r.m. was stirred 1 h at this temperature.Carbonodithioic acid, O-ethyl S-(2-oxoethyl) ester (prepared as reportedin Helv. Chim. Acta, 1992, 907; 0.989 g, 6.02 mmol) in THF (10 mL) wasthen added. The r.m. was stirred for 2 h. Subsequently, the mixture wasquenched with sat. aq. NH₄Cl sol. and extracted with EtOAc. The organiclayer was separated, dried (MgSO₄), filtered and the solvent wasevaporated. The residue was purified by flash column chromatography(silica; heptane/EtOAc 100/0 to 75/25) gave intermediate 80 (0.88 g,47%; mixture of E and Z isomers).

b) Preparation of Intermediate 81

To N-methylpiperazine (25 mL, 225 mmol) at 0° C., intermediate 80 (5 g,16 mmol) in DCM (8 mL) was added dropwise, under a N₂ flow. The r.m. wasstirred at r.t. and the reaction as followed by TLC. When conversion tothe free thiol was observed, the r.m. was cooled to 0° C. and HCl (37%in water, 35 mL, 419 mmol) was added cautiously dropwise. The r.m. wasstirred 1 h at r.t., then diluted with water and extracted with DCM. Thecombined organic layers were dried, filtered and evaporated to give acrude, which was purified by flash column chromatography (silica;DCM/MeOH 100/0 to 95/5). The product fractions were collected and thesolvent evaporated, to afford intermediate 81 (1.7 g, 51%).

c) Preparation of Intermediate 82

To a solution of intermediate 81 (0.847 g, 4.11 mmol) in THF (23 mL) wasadded dropwise butyl lithium (2.5M in hexane, 2.1 mL, 5.34 mmol) at −30°C. under N₂ atmosphere. After 20 min of stirring at this temperature,DMF (2.5 mL) was added dropwise. The r.m. was then allowed to warm up tor.t. for 1 h, quenched with sat. NH₄Cl sol., then extracted with EtOAc.The organic layer was washed with brine, dried, filtered andconcentrated in vacuo to give a crude, which was used without furtherpurification in the subsequent step (0.815 g).

d) Preparation of Intermediate 83

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 30, intermediate 83 was obtained startingintermediate 82,

Example A27 a) Preparation of Intermediate 84

3-(Trifluoromethyl)cyclohexanone (0.79 g, 4.76 mmol) was dissolved inDMF (20 mL). Ethyl cyanoacetate (0.56 mL, 5.23 mmol) and sulfur (0.324g, 9.51 mmol) were added, followed by L-proline (0.055 g, 0.48 mmol),and the r.m. stirred for 24 h at 60° C. After this time the mixture wascooled to r.t., diluted with EtOAc and washed with water and brine. Theorganic extracts were dried over MgSO₄, filtered and the solventevaporated in vacuo to afford a crude, which was purified by flashcolumn chromatography (silica; heptanes/EtOAc 100/0 to 75/25). Theproduct fractions were collected and the solvent was evaporated to yieldintermediate 84 (0.962 g, 69%).

b) Preparation of Intermediate 85

tert-Butyl nitrite (7.4 mL, 6.32 mmol) and copper (II) chloride (1.60 g,11.88 mmol) were dissolved in MeOH (48 mL). To this mixture intermediate84 (0.962 g, 3.28 mmol) was added in one portion and the reaction wasstirred for 1 h, then quenched with sat. aq. NH₄Cl sol. and the solventevaporated. The resulting slurry was partitioned between DCM and water.The organic sol. was separated and dried over MgSO₄, filtered and thesolvent was evaporated in vacuo to give a crude, which was used withoutfurther purification for the subsequent reaction (0.9 g).

c) Preparation of Intermediate 86

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 34, intermediate 86 was obtained startingintermediate 85.

Example A28 a) Preparation of Intermediate 87

3,4-Dihydro-2H-pyran (1.7 mL, 19.02 mmol) in THF (10 mL) was added to asolution of 2-(3-thienyl)ethanol (2 mL, 18.11 mmol) in THF (10 mL).p-Toluenesulfonic acid (125 mg, 0.72 mmol) was then added and themixture was stirred at r.t. overnight. Additional 3,4-dihydro-2H-pyran(0.2 eq) was added and the mixture was stirred for 1 h at r.t., then thesolvent was removed in vacuo and the residue dissolved in EtOAc, washedwith aq. K₂CO₃ sol. and water. The organic layers were combined, driedover MgSO₄ and the solvent evaporated to give a crude, which waspurified by flash column chromatography (silica; DCM/EtOAc 100/0 to75/25) to afford intermediate 87 (2.80 g, 73%).

b) Preparation of Intermediate 88

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 69 and intermediate 72, intermediate 88 wasobtained starting from intermediate 87.

c) Preparation of Intermediate 89

To a solution of intermediate 88 (0.64 g, 2.17 mmol) in MeOH (26 mL) wasadded p-toluensulfonic acid (0.187 g, 1.09 mmol). The r.m. was thenstirred at r.t for 90 min. After this time the mixture was concentratedin vacuo and the residue was dissolved in DCM. The solution was washedwith aq. NaHCO₃ sol., dried over MgSO₄ and concentrated in vacuo toafford intermediate 89 (0.417 g, crude material).

d) Preparation of Intermediate 90

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 66, intermediate 90 was obtained starting fromintermediate 89.

Example A29 a) Preparation of Intermediate 91

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 28, in the presence of a thiophene solution inTHF, intermediate 91 was obtained starting from methyl4-amino-5-chloro-2,3-dihydrobenzofuran-7-carboxylate (described in ACSSymposium Series, 870 (Chemical Process Research), 125-139; 2004).

b) Preparation of Intermediate 92

Water (60 mL) was stirred at 0° C. Sulfuric acid (30 mL, 55 mmol) wasadded dropwise at 0° C. Intermediate 91 (19.3 g, 100 mmol) was added. Asolution of sodium nitrite (7.6 g, 110 mmol) in water (16 mL) was addeddropwise at 0° C. The r.m. was stirred for 30 min at 0° C., then stirredfor 1 h at 40° C. The precipitate obtained was filtered off, washed withwater, and the residue was suspended in hot toluene. The suspension wascooled and the resulting precipitate was filtered off and dried toafford intermediate 92 (16.1 g), used as such in the subsequent reactionstep.

c) Preparation of Intermediate 93

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 24,intermediate 75, intermediate 53, intermediate 33 and intermediate 30,intermediate 93 was obtained starting from intermediate 92.

Example A30 a) Preparation of Intermediate 94

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 24,intermediate 89 and intermediate 23, intermediate 94 was obtainedstarting from intermediate 8 and commercially available2-(2-bromoethoxyl)tetrahydro-2H-pyran.

b) Preparation of Intermediate 95

3-(Trifluoromethyl)piperidine (0.12 mL), 0.90 mmol), intermediate 94(0.34 g, crude material) and DIPEA (0.23 mL, 1.35 mmol) indimethylacetamide (5 mL) were stirred for 5 h at 80° C.Tetrabutylammonium iodide (0.066 g, 0.18 mmol) was then added and ther.m. heated overnight at 90° C. After this time the r.m. was allowed tocool down to r.t. and sat. NaHCO₃ sol. and EtOAc were added. The aqueousphase was extracted once more with EtOAc. The combined organic layerswere dried over MgSO₄, filtered and the solvent evaporated. The crudewas purified by flash column chromatography (silica; DCM/MeOH 100/0 to93/7). The desired fractions were collected and concentrated in vacuo toyield intermediate 95 as a brown oil (0.392 g).

Example A31 a) Preparation of Intermediates 96 and 97

1-(Prop-2-en-1-yloxy)-3-(trifluoromethyebenzene (3.9 g, 19.29 mmol) washeated at 240° C. for 1 h under microwave irradiation. The crudeobtained was purified by flash column chromatography (silica; DCM/EtOAc100/0 to 50/50). The desired fractions were collected and concentratedin vacuo to yield a mixture of intermediate 96 and 97, which was usedwithout further purification in the subsequent reaction.

b) Preparation of Intermediates 98 and 99

m-Chloroperbenzoic acid (1.585 g, 6.43 mmol) was added to a solution ofintermediate 96 and intermediate 97 (1.3 g) in chloroform (15 mL). Thereaction was stirred at reflux for 12 h, then it was diluted with sat.NaHCO₃ sol. and extracted with EtOAc. The organic layer was separated,dried over MgSO₄, filtered and the solvents evaporated in vacuo. Thecrude product was purified by flash column chromatography (silica;heptanes/EtOAc 100/0 to 90/10). The desired fractions were collected andconcentrated in vacuo to yield intermediate 98 (0.267 g) andintermediate 99 (0.15 g) as colorless oils.

c) Preparation of Intermediate 100

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 23, intermediate 100 was obtained startingfrom intermediate 98.

d) Preparation of Intermediate 101

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 59, intermediate 101 was obtained startingfrom intermediate 8 and intermediate 100.

Example A32 a) Preparation of Intermediates 102 and 103

To a solution of benzo[b]thiophene-3-carboxylic acid,2-amino-4,5,6,7-tetrahydro-6-(trifluoromethyl)-, ethyl ester (0.20 g,0.68 mmol) in HBr (48% in water, 1.4 mL, 12.27 mmol) at 0° C. a solutionof sodium nitrite (0.047 g, 0.68 mmol) in water (2 mL) was addeddropwise over 45 min. The r.m. was warmed to r.t. and further stirredfor 15 min, then cooled to 0° C. and copper (I) bromide (0.147 g, 1.02mmol) was added portionwise. The mixture was stirred at 0° C. for 15min, at r.t. for 15 min and at 140° C. for 40 min. The r.m. was thencooled to r.t. and neutralised with aq. sat. Na₂CO₃ sol. EtOAc was addedand layers were separated. The organic phase was evaporated and theresidue was purified by flash column chromatography (silica,heptanes/EtOAc 100/0 to 90/10). The product fractions were combined andevaporated in vacuo to give a mixture of intermediate 102 andintermediate 103, to which was added zinc (40 mg, 0.62 mmol). Themixture was heated at reflux in AcOH (4 mL) for 16 h. After cooling, themixture was poured on onto ice and neutralized by cautious addition ofaq. sat. NaHCO₃ sol. The resulting aqueous suspension was extracted withEtOAc (3×100 mL). The combined organic layers were washed with brine,dried over MgSO₄ and concentrated in vacuo to afford intermediate 102(54 mg).

a1) Alternative Preparation of Intermediate 102

tert-Butyl nitrite (1.5 mL, 1.31 mmol) and copper (I) chloride (0.332 g,2.47 mmol) were dissolved in MeOH (10 mL).Benzo[b]thiophene-3-carboxylic acid,2-amino-4,5,6,7-tetrahydro-6-(trifluoromethyl)-, ethyl ester (0.20 g,0.68 mmol) was added in one portion and the reaction was stirred for 1h, then it was quenched with sat. aq. NH₄Cl sol. and the solvent wasevaporated. The resulting slurry was partitioned between DCM and water.The organic layer was separated and dried over MgSO₄, filtered and thesolvent evaporated to give intermediate 102 (0.181 g, crude material).

b) Preparation of Intermediate 195

By following an analogous synthesis protocol as the one reported for thesynthesis of intermediate 30, intermediate 104 was obtained startingfrom intermediate 102.

Example A33 a) Preparation of Intermediate 105

To a stirred solution of 3-cyclopropoxy-5-(trifluoromethyl)benzoic acid(1.21 g, crude) in DMF (25 mL) were added DIPEA (2.4 mL) and HBTU (2.24g, 5.90 mmol) at 0° C. After 20 minutes, N,O-dimethylhydroxylaminehydrochloride (0.53 g, 5.41 mmol) was added and the solution was allowedto come to r.t. and stirred at the same temperature overnight. Sat.NaHCO₃ sol. was added and the solution was extracted with EtOAc. Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuo.The crude product was purified by flash column chromatography (silica;heptanes/EtOAc 100/0 to 50/50) to yield intermediate 105 (1.28 g, 90%).

b) Preparation of Intermediate 106

Methylmagnesium bromide (1.4 M in toluene/THF, 3.5 mL, 4.87 mmol) wasadded to a solution of intermediate 105 (1.28 g) in dry THF (25 mL) at0° C. The r.m. was allowed to come to r.t. and stirred at the sametemperature for 1 h. Additional methylmagnesium bromide (0.2 eq) wasadded. After reaction completion, aq. NH₄Cl sol. and EtOAc were added.The organic layer was separated, dried over MgSO₄, filtered andevaporated in vacuo. The crude product was purified by flash columnchromatography (silica; heptanes/EtOAc 100/0 to 90/10) to affordintermediate 106 (0.93 g, 86%).

c) Preparation of Intermediate 107

By following a synthetic sequence involving procedures similar to theones used for the synthesis of intermediate 29 and intermediate 23,intermediate 107 was obtained starting from intermediate 106.

d) Preparation of Intermediates 108 and 109

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 59, a mixture of intermediate 108 andintermediate 109 was obtained starting from intermediate 8 andintermediate 107. The mixture was purified by flash columnchromatography (silica; heptanes/EtOAc 100/0 to 80/20). The desiredfractions were collected and concentrated in vacuo to yield intermediate108 as a pale brown solid and intermediate 109 as a sticky brown solid.

Example A34 a) Preparation of Intermediate 110

By following a synthetic sequence involving procedures similar to theones used for the synthesis of intermediate 107, intermediate 110 wasobtained starting from commercially available1-(3-chloro-4-(trifluoromethoxy)phenyl)ethanone.

b) Preparation of Intermediates 111 and 112

By following a synthetic procedure similar to the one reported for thesynthesis of intermediate 59, a mixture of intermediate 111 andintermediate 112 was obtained starting from intermediate 8 andintermediate 110. The mixture was purified by flash columnchromatography (silica; heptanes/EtOAc 100/0 to 75/25). The desiredfractions were collected and concentrated in vacuo to yield intermediate111 (0.322 g, 20%) and intermediate 112 (0.33 g, 21%) as pale yellowsolids.

Example A35 a) Preparation of Intermediate 113

Methyl 3-hydroxy-5-(trifluoromethyl)phenylacetate (0.32 g, 1.36 mmol)and bis(1,5-cyclooctadiene)diiridium(I) dichloride (9 mg, 14 μmol) wereadded to a stirred solution of vinyl acetate (0.25 mL, 2.72 mmol) andNa₂CO₃ (86 mg, 0.82 mmol) in toluene (5 mL) while N₂ was bubbled throughthe r.m. The mixture was stirred for 3 h at 100° C. in a sealed tube,then water and EtOAc were added. The aqueous phase was extracted oncemore with EtOAc. The combined organics were dried over MgSO₄, filteredand evaporated. The crude was purified by flash column chromatography(silica; heptanes/EtOAc 100/0 to 90/10). The desired fractions werecollected and concentrated in vacuo to yield intermediate 113 as a paleyellow oil (284 mg, 81%).

b) Preparation of Intermediate 114

To a N₂ flushed round bottom flask, diethyl zinc (1M in heptanes, 8.3mL, 8.3 mmol) was added to DCM (7 mL). The resulting solution was cooledwith an ice bath. TFA (0.6 mL, 7.99 mmol) was added slowly by a syringe.The reaction mixture was then stirred at 0° C. for 10 min. Diiodomethane(0.7 mL, 8.61 mmol) was subsequently added by a syringe and theresulting r.m. was stirred at 0° C. for additional 10 min. Intermediate113 (0.8 g, 3.07 mmol) in DCM (8 mL) was finally added. The reactionmixture was allowed to warm up to r.t. over 30 minutes, then quenchedwith water (15 mL) and 3 N HCl (15 mL). The layers were separated. Theaqueous phase was extracted with EtOAc. The combined organics were driedover MgSO₄, filtered and concentrated. The crude was purified by flashcolumn chromatography (silica; Heptane/EtOAc 100/0 to 90/10). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate 114 a pale yellow oil (0.73 g, 87%).

c) Preparation of Intermediate 115

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 77, intermediate 115 was obtained startingfrom intermediate 114.

d) Preparation of Intermediate 116

By following a synthetic sequence similar to the one reported for thesynthesis of intermediate 24, intermediate 116 was obtained startingfrom intermediate 8 and intermediate 115.

Example A36 a) Preparation of Intermediate 117

Sodium cyanide (0.746 g, 15.23 mmol) was added dropwise to a stirredsolution of 1-(benzyloxy)-3-(chloromethyl)-5-(trifluoromethyl)benzene(3.05 g, 10.15 mmol) in DMF (30 mL) at 0° C. under N₂ atmosphere. Themixture was stirred for 16 h at r.t. Then sat. NaHCO₃ sol. was added andthe mixture extracted with EtOAc. The combined organics were dried overMgSO₄, filtered and concentrated in vacuo. The crude product waspurified by flash column chromatography (silica; hexane/EtOAc 100/0 to80/20). The desired fractions were collected and concentrated in vacuoto yield intermediate 117 as a colorless oil (2.11 g, 71%).

b) Preparation of Intermediate 118

NaOH (50% aq., 4.05 g, 50.64 mmol) was added dropwise to a mixture ofintermediate 117 (2.12 g, 7.23 mmol), 1-bromo-2-chloroethane (2.1 mL,25.32 mmol) and benzyltriethylammonium chloride (0.494 g, 2.17 mmol).The mixture was stirred at 50° C. for 15 h, then water was added and theorganic layer was extracted with EtOAc. The organic phase was washedwith 5% aq HCl sol., then dried over MgSO₄, filtered and the solvent wasremoved in vacuo. The crude product was purified by flash columnchromatography (silica; hexane/EtOAc 100/0 to 90/10). The desiredfractions were collected and concentrated in vacuo to yield intermediate118 as a white solid (1.95 g, 85%).

c) Preparation of Intermediate 119

Intermediate 118 (1.95 g, 6.14 mmol) in AcOH (6 mL) and HCl (37% aq., 20mL) was heated at 95° C. for 15 h in a sealed tube, then the mixture wasdiluted with water and extracted with EtOAc. The organic layer waswashed with water, dried over MgSO₄, filtered and the solventsevaporated in vacuo. The crude material was used as such into thesubsequent reaction step (1.51 g).

d) Preparation of Intermediate 120

Thionyl chloride (1.3 mL, 18.41 mmol) was added to a stirred solution ofintermediate 119 (1.51 g) in chloroform (20 mL) at 0° C., then DMF (48μL) was added. The mixture was stirred overnight at r.t. The solvent wasthen evaporated and the residue was co-distilled with toluene severaltimes. MeOH (20 mL) was added and the mixture was stirred overnight atr.t. The solvent was then evaporated. Sat. NaHCO₃ sol. and EtOAc wereadded and the phases separated. The aqueous phase was extracted oncewith EtOAc, then the combined organic layer was dried over MgSO₄,filtered and evaporated. The crude was purified by flash columnchromatography (silica; heptanes/EtOAc 100/0 to 70/30). The desiredfractions were collected and concentrated in vacuo to yield intermediate120 as a white solid (1.44 g, 91%).

e) Preparation of Intermediate 121

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 113,intermediate 114, intermediate 75, intermediate 76, intermediate 23 andintermediate 24, intermediate 121 was obtained starting fromintermediate 120 and intermediate 18.

Example A37 a) Preparation of Intermediate 122

Hexamethylenetetramine (18.54 g, 132.24 mmol) was added to a mixture of4-chloro-2-fluorophenol (8.5 g, 66.12 mmol) in methanesulfonic acid (50mL, 771.02 mmol) at 0° C. The reaction mixture was then heated to 100°C. After completion of the reaction (1.5 h), the reaction mixture wasallowed to cool to rt and was poured into ice water (50 mL). Theprecipitated yellow solid was collected by filtration and washed withwater. This solid was dissolved in EtOAc, and then washed with water andbrine. The organic phase was dried over MgSO₄, filtered and concentratedto yield intermediate 126 as a yellow oil (5.95 g, 28%), whichsolidified upon standing.

b) Preparation of Intermediate 123

Intermediate 122 (3.17 g, 20.25 mmol) was stirred in DCM (7 mL). ThenBF₃.OEt₂ (0.28 mL, 2.03 mmol) was added to the stirring solution. Thereaction mixture was stirred during 10 min at rt. Ethyl diazoacetate(3.6 mL, 34.84 mmol) in DCM (21 mL) was added dropwise to the reactionmixture, resulting in steady evolution of nitrogen (total addition time10 min) and an increase in temperature. Once gas evolution ceased, thesolvents were evaporated in vacuo. With vigorous stirring, sulfuric acid(1.4 mL) was added dropwise to the oil. The addition is slightlyexothermic. After 20 minutes of vigorously stirring, a solidprecipitated. The acidic reaction mixture was then neutralized by slowaddition of aq. sat. NaHCO₃ sol. The aqueous layer was extracted withEtOAc. The organic layer was then washed with brine, dried over MgSO₄,filtered and concentrated to afford an orange oil. This crude waspurified by flash column chromatography (silica; heptanes/DCM 100/0 to0/100). The desired fractions were collected and concentrated in vacuoto yield intermediate 123 (2.49 g, 55%).

c) Preparation of Intermediate 124

Diisobutylaluminum hydride (1 M in toluene, 22.4 mL, 33.25 mmol) wasslowly added to intermediate 123 (2.49 g, 11.08 mmol) in DCM (37 mL) at−65° C. under N₂ atmosphere. After 20 min, the reaction was carefullyquenched with aq. sat. Rochelle's salt sol. MeOH was added and themixture was diluted with EtOAc and filtered through Celite. Thevolatiles were evaporated and the resulting crude was taken up in EtOAc.Water was added and the organic layer was separated. The organic layerwas washed with water and brine, dried over MgSO₄, filtered andconcentrated to give intermediate 124 (1.84 g, 91%).

d) Preparation of Intermediate 125

Intermediate 125 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 45. Starting fromintermediate 124 (0.21 g, 1.15 mmol) intermediate 125 was obtained as amixture of the mesylate and the chloro derivative (ratio 1:2 accordingto NMR), and the crude was used as such in the next step (0.31 g).

Example A38 a) Preparation of Intermediate 126

Hexamethylenetetramine (19.32 g, 136.47 mmol) was added to a mixture of4-chloro-2-fluorophenol (10 g, 68.24 mmol) in methanesulfonic acid (51.6mL, 796.05 mmol) at 0° C. The reaction mixture was then heated to 100°C. After completion of the reaction (1.5 h), the reaction mixture wasallowed to cool to rt and was poured into ice water. The precipitatedyellow solid was collected by filtration and washed with water. Thissolid was dissolved in DCM, dried over MgSO4, filtered and concentratedto yield intermediate 126 as a yellow oil (7.554 g, 63% yield).

b) Preparation of Intermediate 127

Intermediate 127 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 123. Starting fromintermediate 126 (7.554 g, 43.27 mmol) intermediate 127 was obtained asa pale yellow solid (4.904 g, 47%).

c) Preparation of Intermediate 128

Intermediate 128 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 124. Starting fromintermediate 127 (4.904 g, 20.21 mmol) intermediate 128 was obtained asa white solid (4.095 g, quantitative yield).

d) Preparation of Intermediate 129

Intermediate 129 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 45. Starting fromintermediate 128 (1.368 g, 6.82 mmol) intermediate 129 was obtained andused as such in the next reaction step (2.648 g).

Example A39 a) Preparation of Intermediate 130

Intermediate 129 (1.83 g, 10.02 mmol) was dissolved in DCM (64 mL).Dess-Martin periodinane (6.40 g, 15.09 mmol) was added at 0° C. Thereaction mixture was stirred at rt during 4 h. The reaction mixture wasdiluted with DCM and aq. Na₂S₂O₃ sol. (10%) and aq. sat. NaHCO₃ sol.were added. After 30 min stirring, the mixture was filtered throughCelite and the layers were separated. The organic layer was washedrespectively with aq. sat. NaHCO₃ sol., water and brine, dried overMgSO₄, filtered and concentrated in vacuo to afford intermediate 130(1.55 g, 86%).

b) Preparation of Intermediate 131

Methylmagnesium chloride (3 M in THF, 9.9 mL, 29.90 mmol) was added to asolution of intermediate 130 (1.35 g, 7.47 mmol) in dry THF (15 mL) at−78° C. The r.m. was stirred during 30 min and then warmed to rt. Aq.NH₄Cl sol. and EtOAc were added, The organic layer was separated, driedover MgSO₄, filtered and evaporated in vacuo to afford racemicintermediate 131 (1.2 g, 82%).

c) Preparation of Intermediate 132

Intermediate 132 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 129. Starting fromintermediate 131 (1.18 g, 6.00 mmol) intermediate 132 was obtained andused as such in the next reaction step (1.4 g).

Example A40 a) Preparation of Intermediate 133

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, intermediate 130, intermediate 131and intermediate 132, intermediate 133 was obtained starting fromcommercially available 4-chloro-3-fluorophenol.

Example A41 a) Preparation of Intermediate 134

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, and intermediate 45, intermediate134 was obtained starting from commercially available4-chloro-3-fluorophenol.

Example A42 a) Preparation of Intermediate 135

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, and intermediate 45, intermediate135 was obtained starting from commercially available4-trifluoromethylphenol.

Example A43 a) Preparation of Intermediate 136

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, intermediate 130, intermediate 131and intermediate 132, intermediate 136 was obtained starting fromcommercially available 4-trifluoromethylphenol.

Example A44 a) Preparation of Intermediate 137

Sodium borohydride (3.83 g, 101.31 mmol) and THF (97 mL) were mixed andadded dropwise to dimethylsulfate (9.3 mL, 98.08 mmol) at 0° C. andstirred first for 1 h at this temperature and 4 h at rt until no gasgeneration was observed. A solution of 4-trifluoromethyl salicylic acid(10 g, 48.52 mmol) and trimethylborate (11.0 mL, 98.98 mmol) in THF (49mL) was added dropwise to the rm at rt over 30 min. The mixture wasstirred at the same temperature for 4.5 h. After the reaction wascompleted, H₂O was added slowly at 0° C. and the resulting mixture wasvigorously stirred for 30 min. Then THF was removed on a rotaryevaporator. The residue was extracted with EtOAc (×3) and the combinedorganic layer was washed with sat. aq. NaHCO₃ sol. (×3) and brine (×3).The organic layer was then dried over Na₂SO₄, filtered, and concentratedin vacuo to give intermediate 137 as a crude, which was used as such inthe next reaction (10.12 g, quantitative yield).

b) Preparation of Intermediate 138

Intermediate 137 (9.55 g, 49.70 mmol) and DDQ (11.28 g, 49.70 mmol) weredissolved in DCM (76 mL) and THF (19 mL) at rt. After 4 h, the solventswere evaporated in vacuo and the black oily residue was adsorbed onsilica gel and purified via filtration on a silica plug. The desiredfractions were collected to afford intermediate 138 as a brown solid(8.17 g, 86%).

c) Preparation of Intermediate 139

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124 and intermediate 45, intermediate 139 was obtainedstarting from intermediate 138.

Example A45 a) Preparation of Intermediate 140

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124, intermediate 130, intermediate 131 and intermediate132, intermediate 140 was obtained starting from intermediate 138.

Example A46 a) Preparation of Intermediate 141

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122 andintermediate 123, intermediate 141 was obtained starting fromcommercially available 4-bromo-2-(trifluoromethyl)phenol.

b) Preparation of Intermediate 142

EtOH (400 mL) was added to Pd/C (10%, 1.578 g) under N₂ atm.Intermediate 141 (5 g, 14.83 mmol) was added and the resulting mixturewas stirred at rt under H₂ atm (atmospheric pressure) for 2 h. Themixture was filtered through celite and the filtrate was evaporated invacuo. Water was added and a solid precipitated. This solid wascollected by filtration, washed with water and dried (vacuum oven) toafford intermediate 142 (3.56 g, 93%).

c) Preparation of Intermediate 143

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 124 andintermediate 45, intermediate 143 was obtained starting fromintermediate 142.

Example A47 a) Preparation of Intermediate 144

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124, and intermediate 45, intermediate 144 was obtainedstarting from commercially available 3,5-dichloro-2-hydroxybenzaldehyde.

Example A48 a) Preparation of Intermediate 145

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124, intermediate 130, intermediate 131 and intermediate132, intermediate 145 was obtained starting from commercially available5-(trifluoromethoxy)salicylaldehyde.

Example A49 a) Preparation of Intermediate 146

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124 and intermediate 130, intermediate146 was obtained starting from commercially available4-chloro-3-fluorophenol.

b) Preparation of Intermediate 147

Intermediate 146 (2.2 g, 11.08 mmol), ethylene glycol (9.3 mL, 166.18mmol), p-toluenesulfonic acid (0.09 g, 0.55 mmol) were refluxed intoluene (60 mL) overnight. The solvent was then evaporated and theresidue was dissolved in EtOAc and washed with water. The organic layerwas dried over MgSO₄, filtered and concentrated in vacuo to affordintermediate 147 (2.1 g, 55%), which was used as such in the next step.

c) Preparation of Intermediate 148

tert-Butyl lithium (1.7 M in pentane, 0.36 mL, 0.62 mmol) was addeddropwise to a solution of intermediate 147 (0.1 g, 0.412 mmol) in THF (2mL) at −78° C. The reaction mixture was stirred for 30 min at thistemperature. N-Fluorobenzenesulfonimide (0.195 g, 0.62 mmol) in THF (10mL) was added dropwise. The mixture was stirred at −78° C. during 4 h.The reaction was quenched with water and warmed to rt. The aqueous wasextracted with EtOAc and the combined organic layers were dried overMgSO₄, filtered and concentrated in vacuo. The residue was dissolved inTHF (2 mL) and treated with 1N HCl (2 mL). After 30 min deprotection wascompleted and the solvent was evaporated. The resulting residue wasdissolved in EtOAc and washed with sat. NaHCO₃ sol., water and brine.The organic layer was separated, dried over MgSO₄, filtered andconcentrated in vacuo to afford intermediate 148 (0.1 g), which was usedas such in the next step.

d) Preparation of Intermediate 149

Sodium borohydride (0.035 g, 0.92 mmol) was added to a solution ofintermediate 148 (0.1 g, 0.46 mmol) in MeOH (0.5 mL) at rt. The reactionmixture was stirred for 1 hour at this temperature. Aq. sat NaHCO₃solution was added and the reaction was stirred during 30 min. EtOAc andwater were added. The aqueous was extracted with EtOAc and the combinedorganic layers were washed with water and brine, then dried over MgSO₄,filtered and concentrated in vacuo. The crude product was purified byflash column chromatography to yield intermediate 149 (0.026 g).

e) Preparation of Intermediate 150

Intermediate 150 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 45. Starting fromintermediate 149 (0.026 g, 0.12 mmol) intermediate 150 was obtained andused as such in the next reaction step (0.045 g).

Example A50 a) Preparation of Intermediate 151

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124 and intermediate 45, intermediate 151 was obtainedstarting from commercially available 3-bromo-2-hydroxybenzaldehyde.

Example A51 a) Preparation of Intermediate 152

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124 and intermediate 45, intermediate 152was obtained starting from commercially available3-fluoro-4-(trifluoromethyl)phenol as a mixture of the mesylate and thechloro derivative.

Example A52 a) Preparation of Intermediate 153

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, intermediate 130, intermediate 131and intermediate 132, intermediate 153 was obtained starting fromcommercially available 3-fluoro-4-(trifluoromethyl)phenol.

Example A53 a) Preparation of Intermediate 154

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124 and intermediate 45, intermediate 152was obtained starting from commercially available4-fluoro-3-(trifluoromethyl)phenol as a mixture of the mesylate and thechloro derivative.

Example A54 a) Preparation of Intermediate 155

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, intermediate 130, intermediate 131and intermediate 132, intermediate 153 was obtained starting fromcommercially available 4-fluoro-3-(trifluoromethyl)phenol as a mixtureof the mesylate and the chloro derivative (ratio 1:2 according to NMR).

Example A55 a) Preparation of Intermediate 156

5-Chloro-2-fluorobenzotrifluoride (8.5 g, 42.81 mmol) in THF (57 mL) wastreated with tetramethylethylenediamine (9.3 mL, 62.33 mmol) and cooleddown to −78° C. n-Butyl lithium (1.6 M in hexane, 22.2 mL, 55.53 mmol)was added dropwise. After stirring at −78° C. for 90 min, the mixturewas treated with DMF (4.4 mL) and stirred further 30 min. The reactionmixture was allowed to wam to rt and was quenched with aq. sat NH₄Clsolution and diluted with Et₂O. The organic layer was washed with brine,dried over MgSO₄, filtered and evaporated. The residue was then treatedwith sodium methoxide (30% in MeOH, 80 g, 1480.82 mmol). The reactionwas stirred overnight at rt. Water was added and the aqueous phase wasextracted with Et₂O. The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo to afford an oil. This crude waspurified by flash column chromatography (silica; heptanes/DCM 100/0 to50/50). The desired fractions were collected and concentrated in vacuoto yield intermediate 156 as a yellow oil (8.23 g, 85%).

b) Preparation of Intermediate 157

Boron tribromide (1 M in DCM, 19.3 mL, 16.33 mmol) was added dropwise toa solution of intermediate 156 (3.84 g, 16.11 mmol) in DCM (38 mL) at−78° C. The reaction was stirred at rt overnight. Water (20 mL) wasadded at −41° C. and the mixture was allowed to warm to rt. EtOAc wasadded and the organic phase was separated. The aqueous phase wasextracted with EtOAc. The combined organic layers were dried over MgSO₄,filtered and concentrated in vacuo. This crude was purified by flashcolumn chromatography (silica; heptanes/DCM 100/0 to 50/50). The desiredfractions were collected and concentrated in vacuo to yield intermediate157 as an orange oil (2.33 g, 64%), which solidifies upon standing.

c) Preparation of Intermediate 158

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124 and intermediate 45, intermediate 158 was obtainedstarting from intermediate 157.

Example A56 a) Preparation of Intermediate 159

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124, intermediate 130, intermediate 131and intermediate 132, intermediate 159 was obtained starting fromcommercially available 4-chloro-2-fluorophenol.

Example A57 a) Preparation of Intermediate 160

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 122,intermediate 123, intermediate 124 and intermediate 45, intermediate 160was obtained starting from commercially available 3,4-dichlorophenol.

Example A58 a) Preparation of Intermediate 161

3-Trifluoromethylpiperidine (0.36 mL, 2.73 mmol) was added to a solutionof bromoacetyl bromide (0.24 mL, 2.73 mmol) and potassium carbonate(0.47 g, 3.41 mmol) in THF (9 mL) at 0° C. The reaction mixture was thenwarmed up to rt and stirred 24 h. Water was added and the aqueous layerwas extracted with EtOAc. The combined organic layers were washed withaq. sat. NaHCO₃ and brine, dried over MgSO₄, filtered and concentratedin vacuo. This crude was purified by flash column chromatography(silica; heptanes/DCM 100/0 to 60/40). The desired fractions werecollected and concentrated in vacuo to yield intermediate 161 (0.29 g,39%).

Example A59 a) Preparation of Intermediate 162

3-Chloro-2-methylpropene (2.35 g, 26 mmol) was added dropwise to asolution of 2-bromochlorophenol (4.15 g, 20 mmol) and K₂CO₃ (5.53 g,39.99 mmol) in DMF (100 mL) at rt. The reaction mixture was stirredovernight at 70° C. After cooling down to rt, the reaction mixture wasdiluted with EtOAc and washed twice with water and once with brine. Theorganic layer was dried over MgSO₄, filtered and concentrated in vacuoto afford intermediate 162, which was used as such in the next reaction.

b) Preparation of Intermediate 163

To a microwave vial equipped with a magnetic stir bar was addedintermediate 162 (0.20 g, 0.76 mmol). The vial was purged with argon for5 minutes, after which Pd(Q-Phos)2 (0.058 g, 0.038 mmol), potassiumiodide (0.25 g, 1.53 mmol) and toluene (15 mL) were added. The vial wascapped and added to an oil bath pre-heated to 100° C. After stirring for6 hours, extra Pd(Q-Phos)2 (0.058 g, 0.038 mmol) (prepared as describedin Org. Lett. 2010, 12, 3332) was added and the reaction mixture wasstirred at 100° C. over the weekend. The vial was cooled and thecontents filtered over a pad of silica gel, washing with ether. Thecrude material was loaded on to a silica gel column and purified byflash chromatography. This crude was purified by flash columnchromatography (silica; heptanes/EtOAc 100/0 to 90/10). The desiredfractions were collected and concentrated in vacuo to yield racemicintermediate 163 (0.11 g, 45%).

Example A60 a) Preparation of Intermediate 164

Zinc iodide (0.45 g, 1.42 mmol) was added to a solution of6-chlorochroman-4-one (5 g, 27.38 mmol) in DCM (20 mL). Thentrimethylsilyl cyanide (7.05 g, 71.1 mmol) was added dropwise and thereaction mixture was stirred at rt during 15 hours. The reaction mixturewas washed three times with sat. aq. NaHCO₃ sol. The organic layer wasdried over MgSO₄, filtered and concentrated in vacuo. The crude waspurified by flash column chromatography (silica; heptanes/DCM 100/0 to60/40). The desired fractions were collected and concentrated in vacuoto yield intermediate 164 (5.83 g, 76%). b) Preparation of Intermediate165

Intermediate 164 (3.8 g, 13.48 mmol) was stirred in acetic acid (15 mL)and HCl (15 mL) and then tin (II) chloride dihydrate (9.13 g, 40.45mmol) was added. The reaction mixture was stirred at 125° C. during 24hours. Water was added to the reaction mixture and the aqueous layer wasthen extracted with DCM (3×). The combined organic layers were driedover MgSO₄, filtered and concentrated in vacuo. The crude was purifiedby flash column chromatography (silica, DCM/MeOH 100/0 to 95/5). Thedesired fractions were collected and concentrated in vacuo to yieldintermediate 165 (1.97 g, 69%).

c) Preparation of Intermediate 166

LiAlH₄ (1 M in THF, 26.5 mL, 26.52 mmol) was added to a solution ofintermediate 165 (1.97 g, 8.84 mmol) in THF (45 mL) at −20° C. and thenthe reaction mixture was stirred at rt for 1 h. The r.m. was then cooledto −70° C. and water (4 mL) was carefully added dropwise followed by 1NNaOH (4 mL). THF (40 mL) was then added and the rm was stirred until itreached rt. The reaction mixture was filtered and the solid was washedwith DCM. The filtrate was evaporated in vacuo to afford intermediate166 (1.45 g, 83%).

d) Preparation of Intermediate 167

Intermediate 167 was prepared following a synthetic procedure similar tothe one reported for the synthesis of intermediate 45. Starting fromintermediate 166 (3.2 g, 16.11 mmol) racemic intermediate 167 wasobtained and used as such in the next step.

Example A61 a) Preparation of Intermediate 168

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 123,intermediate 124 and intermediate 45, intermediate 168 was obtainedstarting from commercially available5-(trifluoromethoxy)salicylaldehyde.

Example A62 a) Preparation of Intermediate 169

Trimethylsilyl cyanide (17.7 mL, 142 mmol) was added to a solution of2-fluoro-5-(trifluoromethyl)benzaldehyde (25 g, 130 mmol) in DCM (100mL) and DABCO (1 mL) at such rate that the mixture was maintained at agentle reflux. After 1 h at rt, the reaction mixture was treated withwater (3×50 mL) and brine (50 mL). The organic layer was dried overMgSO₄, filtered and concentrated in vacuo to yield intermediate 169 asan oil (34.7 g, 92%).

b) Preparation of Intermediate 170

A mixture of intermediate 169 (31.7 g, 109 mmol) in water (25 mL) wastreated with HCl (37% in water, 75 mL, 989 mmol) and heated at refluxduring 2 h. The r.m. was cooled down, diluted with ice water (300 mL),treated with NaOH (50% in water) until pH basic and washed with DCM(2×30 mL). The aqueous layer was acidified with conc HCl until pH=1 andextracted with DCM (3×250 mL). The combined organic layers were dried,filtered and evaporated to afford intermediate 170 as an oil (23.6 g,91%), which solidifies upon standing.

c) Preparation of Intermediate 171

Intermediate 170 was dissolved in EtOH (500 mL). Sulfuric acid (10 mL)was added and the r.m. stirred overnight at reflux. The solvent wasevaporated in vacuo, DCM was added and the mixture cooled with an icebath. Aq. sat. NaHCO₃ sol. was added carefully until pH ˜8. The organiclayer was separated, dried over MgSO₄, filtered and concentrated invacuo to afford intermediate 171 as an oil (23.8 g, 88%).

d) Preparation of Intermediate 172

A solution of intermediate 171 (23.8 g, 89.4 mmol) in 1,4-dioxane (250mL) was treated with MnO₂ (60 g, 690 mmol) and stirred at reflux for 3 hand then at rt over the weekend. The reaction mixture was filtered overa small plug of Dicalite and concentrated in vacuo to affordintermediate 172 as an oil (18.5 g, 78%).

e) Preparation of Intermediate 173

A stirred solution of intermediate 172 (18.5 g, 70 mmol) in EtOH (150mL) was treated with hydroxylamine hydrochloride (5.84 g, 84 mmol) andsodium acetate (8.62 g, 105 mmol). The reaction mixture was heated at50° C. for 5 h and then at rt for 16 h. The reaction mixture wasfiltered and concentrated in vacuo. The residue was treated with EtOAc(300 mL) and water (1 L) and the layers were separated. The aqueouslayer was extracted with EtOAc. The combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue was purified by flash column chromatography (silica; DCM/MeOH100/0 to 95/5) to yield intermediate 173 as a white solid (17.6 g, 90%).

f) Preparation of Intermediate 174

K₂CO₃ (10 g, 72.4 mmol) was added to a solution of intermediate 173 (14g, 50.1 mmol) in DMSO (50 mL) and the reaction mixture was stirred at rtfor 16 h. The reaction mixture was diluted with EtOAc (300 mL) and water(100 mL) and the layers were separated. The aqueous layer was extractedwith EtOAc (3×200 mL). The combined organic layers were washed withwater (2×100 mL), brine (100 mL), dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by flash columnchromatography (silica; DCM/MeOH 100/0 to 95/5) to yield intermediate174 as a white solid (9.9 g, 76%).

g) Preparation of Intermediate 175

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 40 andintermediate 45, intermediate 175 was obtained starting fromintermediate 174.

Example A66 a) Preparation of Intermediate 176

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 40 andintermediate 45, intermediate 176 was obtained starting from6-bromo-chroman-2-carboxylic acid methyl ester.

Example A67 a) Preparation of Intermediate 177

Ethyl cyanoacetate (0.6 mL, 5.23 mmol) and sulphur (0.32 g, 9.51 mmol)were added to 3-(trifluoromethyl)cyclohexanone (0.79 g, 4.76 mmol) inDMF (20 mL). Then L-proline (0.054 g, 0.47 mmol) was added and thereaction mixture was stirred at 60° C. for 24 h. After cooling to rt,the reaction mixture was diluted with EtOAc and washed with H₂O andbrine. The organic layer was dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by flash column chromatography(silica; heptanes/EtOAc 100/0 to 75/25) to yield intermediate 177 (0.96g, 69%).

b) Preparation of Intermediate 178

tert-Butyl nitrite (7.35 mL, 6.32 mmol) and copper (II) chloride (1.60g, 11.88 mmol) were dissolved in MeOH (47 mL). To this mixtureintermediate 177 (0.962 g, 3.28 mmol) was added in one portion and thereaction was stirred for 1 h, then quenched with sat. aq. NH₄Cl and thesolvent evaporated. The resulting slurry was partitioned between DCM andwater. The organic sol. was separated and dried over MgSO₄, filtered andthe solvent was evaporated in vacuo to give a crude, which was usedwithout further purification for the subsequent reaction (0.9 g).

c) Preparation of Intermediate 179

By following a synthetic sequence involving procedures similar to theones used for the synthesis of (in the order) intermediate 166 andintermediate 45, intermediate 179 was obtained starting fromintermediate 178.

B. Preparation of the Final Compounds Example B1 a) Preparation ofCompound 1

DIAD (0.039 mL, 0.20 mmol) was added to a stirred solution ofintermediate 25 (70 mg, crude material) and TPP (52 mg, 0.20 mmol) indry THF (20 mL) under N₂ at 0° C. The mixture was stirred at r.t. for 3h, then the solvents were evaporated in vacuo. The product was purifiedby flash column chromatography (silica; DCM/MeOH 100/0 to 90/10). Thedesired fractions were collected and concentrated in vacuo. The compoundwas re-dissolved in DCM and 1.1 eq. of 4N HCl in dioxane was added. Thesolvent was evaporated and the solid triturated with DIPE to yield togive compound 1 as a beige solid (4 mg).

Example B2 a) Preparation of Compounds 2, 3 and 4

Intermediate 18 (429 mg, 1.661 mmol) was stirred in DMF (20 mL) under N₂atmosphere. NaH (146 mg, 3.66 mmol) was added and the r.m. was stirredfor 10 min. Intermediate 30 (390 mg, crude material) was added and themixture was stirred at r.t. for 3 h. Ice was added and the solvents wereevaporated. Water was added and the product was extracted with EtOAc.The organic layer was washed with brine, dried over MgSO₄, filtered andevaporated. The product was purified by flash column chromatography(silica; DCM/MeOH 97/3 to 90/10, then DCM/(7 N NH₃ in MeOH) 90/10). Thepure fractions were collected and the solvent evaporated in vacuo, togive compound 2 (500 mg), which was separated into diastereoisomers byPrep HPLC (Stationary phase: RP SunFire Prep C18 OBD-10 μm, 30×150 mm;Mobile phase: 0.25% NH₄HCO₃ solution in water/MeOH), yielding compound 3(114 mg) and compound 4 (69 mg).

Example B3 a) Preparation of Compounds 5, 6 and 7

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 andintermediate 34, compound 5 (240 mg) was obtained. Compound 5 was thenseparated into diastereoisomers by Prep SFC (Stationary phase: ChiralcelDiacel OD 20×250 mm; Mobile phase: CO₂, iPrOH with 0.2% iPrNH₂). Thedesired fractions were collected, the solvent evaporated in vacuo, theresidue dissolved in MeOH and evaporated again. The two fractions weresuspended in DIPE, filtered and dried in vacuo at 50° C., to affordcompound 6 (57 mg) and compound 7 (49 mg).

Example B4 a) Preparation of Compound 14

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 and3-(bromomethyl)-5-chloro-1,2-benzisoxazole compound 14 was obtained.

Example B5 a) Preparation of Compound 15

Intermediate 18 (287 mg, 1.11 mmol), NaH (89 mg, 2.23 mmol) and18-crown-6 (197 mg, 0.75 mmol) were stirred in dry THF (5 mL) at 70° C.for 1 h under N₂ atmosphere. The r.m. was cooled to r.t. and thenintermediate 41 (458 mg, 1.11 mmol) in DMF (3 mL) was added. The mixturewas then heated to 90° C. and allowed to react at this temperature for24 h. Water was then added and the product was extracted with EtOAc. Thephases were separated, the organic layer was dried over MgSO₄, filteredand evaporated. The crude material was purified by Prep HPLC (Stationaryphase: RP Vydac Denali C18-10 μm, 200 g, 5 cm; Mobile phase: 0.25%NH₄HCO₃ solution in water/acetonitrile). The desired fractions werecollected, the solvent was evaporated, the residue dissolved in MeOH andthe solvent evaporated again, yielding compound 15 (12 mg, 2%).

Example B6 a) Preparation of Compounds 17 and 18

By following a procedure similar to the one reported for the synthesisof compound 15 (Example B5), starting from intermediate 18 andintermediate 49 a mixture of compound 17 and compound 18 was obtained.The mixture was separated into pure diastereoisomers by Prep HPLC(Stationary phase: RP SunFire Prep C18 OBD-10 μm, 30×150 mm; Mobilephase: 0.25% NH₄HCO₃ solution in water, MeOH), yielding compound 17 (6%yield) and compound 18 (5% yield) as foams.

Example B7 a) Preparation of Compounds 20 and 21

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 and a mixtureof intermediates 55 and 56, a mixture of compound 20 and compound 21 wasobtained. The mixture was separated in the single regioisomers by PrepHPLC (Stationary phase: RP SunFire Prep C18 OBD-10 μm, 30×150 mm; Mobilephase: 0.25% NH₄HCO₃ solution in water/acetonitrile). The fractionscontaining the products were collected and the solvent evaporated invacuo. The residue was suspended from DIPE, precipitated, filtered anddried in vacuo to afford compound 20 (48 mg, 10%) and compound 21 (20mg, 4%).

Example B8 a) Preparation of Compound 22

MeOH (40 mL) was added to 10% Pd/C (50 mg) under N₂ atmosphere.Thiophene solution (0.4% in MeOH) was added and the resulting mixturestirred under H₂ atmosphere for 30 min. Compound 20 (60 mg, 0.12 mmol)and potassium acetate (24 mg, 0.25 mmol) were added and the r.m. stirredat 25° C. under H₂ atmosphere until 1 eq. of H₂ was absorbed. Thereaction mixture was then filtered over dicalite. The solvent wasevaporated in vacuo and the residue purified by flash columnchromatography (silica; DCM/MeOH 100/0 to 95/5). The product fractionswere collected and the solvent was evaporated. The product was suspendedin DIPE and dried in vacuo at 50° C., to afford compound 22 (24 mg,48%).

Example B9 a) Preparation of Compound 23

Intermediate 18 (150 mg, 0.58 mmol), NaH (26 mg, 0.64 mmol) and15-crown-5 (0.12 ml, 0.58 mmol) were stirred in dry DMF (7 mL) at r.t.for 1 h under N₂, then intermediate 58 (186 mg, 0.61 mmol) in DMF (2 ml)was added and the mixture stirred at r.t. After 90 min the reaction wasquenched with water and extracted with EtOAc. The combined organiclayers were dried over MgSO₄, filtered and the solvent evaporated, togive a crude which was purified by flash column chromatography (silica;DCM/MeOH 100/0 to 95/5). The desired fractions were collected and thesolvent was evaporated yielding compound 23 (28 mg, mixture ofdiastereomers in a 8:1 ratio (LCMS)).

Example B10 a) Preparation of Compound 32

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 and3-phenoxybenzyl chloride compound 32 was obtained. After purification byflash column chromatography (silica; DCM/MeOH 99/1 to 95/5) the oilobtained after evaporation of the solvent was dissolved in MeOH.Subsequently, the compound was converted into the HCl salt. The saltobtained was recrystallized from Et₂O, to yield compound 32 (47%).

Example B11 a) Preparation of Compounds 35, 36 and 37

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 andintermediate 86, compound 35 (626 mg, mixture of diastereoisomers) wasobtained. The mixture was separated into the single diastereoisomers byPrep SFC (Stationary phase: Chiralpak Diacel AD 30×250 mm; Mobile phase:CO₂, EtOH with 0.4% iPrNH₂), yielding compound 36 (253 mg, 31%) andcompound 37 (266 mg, 33%).

Example B12 a) Preparation of Compounds 45, 46 and 47

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 andintermediate 104, 25 mg of compound 45 (mixture of diastereomers) wasobtained. The mixture was separated into the single diastereoisomers byPrep SFC (Stationary phase: Chiralpak Diacel OJ 20×250 mm; Mobile phase:CO₂, MeOH with 0.4% iPrNH₂). The desired fractions were collected,evaporated, dissolved in MeOH and evaporated again, yielding compound 46(5 mg, 7%) and compound 47 (6 mg, 8%).

Example B13 a) Preparation of Compound 51

Pd₂(dba)₃ (25 mg, 0.027 mmol) and tetramethyl di-tBuXPhos (23 mg, 0.047mmol) were added to an oven-dried vial under N₂ atm and the vial wassealed. Dry toluene (10 mL) and dry dioxane (2 mL) were added and theresulting dark purple mixture was stirred at 120° C. for 3 min.4-Methylimizazole (110 mg, 1.342 mmol) and K₃PO₄ (285 mg, 1.342 mmol)were added to a second oven-dried vial under N₂ atmosphere and the vialwas sealed. Then, intermediate 111 (322 mg, 0.671 mmol) and the premixedcatalyst solution were added to the second vial. The reaction mixturewas stirred at 120° C. for 5 h, then it was cooled to room temperature,diluted with EtOAc, washed with brine, dried over MgSO₄, filtered andconcentrated. The crude was purified by flash column chromatography(silica; DCM/MeOH 100/0 to 96/4). The desired fractions were collectedand concentrated in vacuo. The product (92 mg) was dissolved in EtOAc (2mL), then HCl (4 M in dioxane, 0.053 mL, 0.21 mmol) was added to obtainthe hydrochloride. The solvent was evaporated and the product wastriturated with Et₂O to yield 66 mg of compound 51 as a pale orangesolid.

Example B14 a) Preparation of Compounds 57 and 58

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 andintermediate 132, 1.65 g of a mixture of diastereomers 57 and 57 wasobtained. The mixture was separated into the single diastereoisomers byPrep HPLC (Stationary phase: XBridge C18_(—)3.5 um, Mobile phase: 0.2%NH₄HCO₃ in water, MeOH). The desired fractions were collected,evaporated, dissolved in MeOH and evaporated again, yielding compound 57(150 mg, 8%) and compound 58 (329 mg, 18%).

Example B15 a) Preparation of Compounds 65 and 66

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 andintermediate 133, 1 g of a mixture of diastereomers 65 and 66 wasobtained. The crude was purified by flash column chromatography (silica;DCM/MeOH 100/0 to 95/5). The desired fractions were collected,evaporated, dissolved in MeOH and evaporated again, yielding compound 65(0.45 g, 22%) and compound 66 (0.42 g, 20%).

Example B16 a) Preparation of Compounds 89 and 90Ivelter_(—)2326

By following a procedure similar to the one reported for the synthesisof compound 2 (Example B2), starting from intermediate 18 andintermediate 153, a mixture of diastereomers 89 and 90 was obtained (429mg). The mixture was separated into the single diastereoisomers by PrepSFC (Stationary phase: Chiralpak Diacel AD 30×250 mm; Mobile phase: CO₂,EtOH with 0.2% iPrNH₂). The desired fractions were collected,evaporated, dissolved in MeOH and evaporated again, yielding compound 89(25 mg, 4%) and compound 90 (54 mg, 8%).

Example B17 a) Preparation of Compound 100

Intermediate 18 (1.48 g, 5.72 mmol) and lithium bromide (0.50 g, 5.72mmol) were stirred in dry DMF (180 mL) at r.t. under N₂. NaH (1.37 g,34.33 mmol) was added and the r.m. was stirred for 10 min. Intermediate167 (1.9 g, 6.87 mmol) was added and the mixture was stirred at r.t. for1 week. Two drops of water were added and the solvents were evaporated.Water was added and the aqueous layer was extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered and the solventevaporated, to give a crude which was purified by flash columnchromatography (silica; DCM/MeOH, 98/2 to 96/4). The desired fractionswere collected and the solvent was evaporated yielding compound 100 (50mg, 2%).

By using analogous reaction protocols as described in the foregoingexamples, the compounds listed in the Tables below have been prepared.

‘Co. No.’ means compound number. ‘cb’ means covalent bond.

‘Pr.’ refers to the Example number in analogy to which protocol thecompound was synthesized.

In case no specific stereochemistry is indicated for a stereocenter of acompound, this means that the compound was obtained as a mixture of theR and the S enantiomers. “HCl salt” means hydrochloric acid salt; theexact number of equivalents of HCl was not determined

In case no salt form is indicated, the compound was obtained as a freebase.

TABLE 1a

Salt forms/ Stereo- chemistry/ Co. Optical No. Pr. R¹ L R² R³ R⁴ R⁵Rotation (OR)  8 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  9 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  38 B2 

CH₃ H CH₃ H R-enantiomer OR: −42.91° (589 nm; 20° C.; 0.55 w/v %; DMF) 39 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  10 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −5.40° (589 nm; 20°C.; 0.5 w/v %; DMF) 11 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  12 B2 

CH₂ CH₃ H CH₃ H R-enantiomer HCl salt  13 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  14 B4 

CH₂ CH₃ H CH₃ H R-enantiomer  16 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  19 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: +8.48° (589 nm; 20° C.; 0.495 w/v %;DMF)  20 B7 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −85.14° (589 nm; 20° C.; 0.249 w/v %;DMF)  21 B7 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −65.52° (589 nm; 20° C.; 0.174 w/v %;DMF)  22 B8 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −78.37° (589 nm; 20° C.; 0.245 w/v %;DMF)  24 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −34.93° (589 nm; 20° C.; 0.375 w/v %;DMF)  25 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: +14.04° (589 nm; 20° C.; 0.4415 w/v %;DMF)  26 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −37.29° (589 nm; 20° C.; 0.48 w/v %;DMF)  28 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −11.63° (589 nm; 20° C.; 0.49 w/v %;DMF)  29 B2 

CH₂ CH₃ H CH₃ H R-enantiomer OR: −7.45° (589 nm; 20° C.; 0.725 w/v %;DMF)  31 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  32 B10

CH₂ CH₃ H CH₃ H R-enantiomer HCl salt  33 B2 

CH₂ CH₃ H CH₃ H R-enantiomer HCl salt  41 B2 

CH₃ H CH₃ H R-enantiomer  42 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  44 B13

CH₂ H H CH₃ H Mixture of R and S  40 B13

CH₃ H CH₃ H R-enantiomer HCl salt  53 B13

CH₃ H CH₃ H R-enantiomer HCl salt  54 B2 

CH₂ H H CH₃ H  55 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  56 B2 

CH₂ H H CH₃ H  59 B2 

H H CH₃ H Mixture of R and S  60 B2 

H H CH₃ H R or S enantiomer  61 B2 

H H CH₃ H S or R enantiomer  62 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  63 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  64 B2 

CH₂ H H CH₃ H  67 B5 

H H CH₃ H S or R enantiomer  68 B5 

H H CH₃ H R or S enantiomer  69 B2 

H H CH₃ H S or R enantiomer  70 B2 

H H CH₃ H R or S enantiomer  71 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  72 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  73 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  74 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  75 B2 

CH₂ H H CH₃ H  76 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  77 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  81 B2 

H H CH₃ H S or R enantiomer  82 B2 

H H CH₃ H R or S enantiomer  83 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  84 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  85 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  88 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  93 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  94 B2 

CH₂ H H CH₃ H  97 B2 

CH₂ CH₃ H CH₃ H R-enantiomer  98 B2 

CH₃ H CH₃ H R-enantiomer  99 B5 

CH₂ H H CH₃ H 101 B2 

CH₂ CH₃ H CH₃ H R-enantiomer 104 B2 

CH₂ CH₃ H CH₃ H R-enantiomer

TABLE 1b Co. No. Pr. Structure Salt forms  1 B1 

HCl salt  2 B2 

 3 B2 

 4 B2 

 5 B3 

 6 B3 

 7 B3 

 15 B5 

 17 B6 

 18 B6 

 34 B2 

 35 B11

 36 B11

 37 B11

 45 B12

 46 B12

 47 B12

 48 B13

HCl salt  49 B13

HCl salt  50* B13

HCl salt  51 B13

HCl salt  52 B13

HCl salt  23 B9 

 27 B2 

 30 B2 

HCl salt  43 B13

HCl salt  57 B14

 58 B14

 65 B15

 66 B15

 78 B2 

 79 B2 

 80 B2 

 86 B2 

 87 B2 

 88 B2 

 89 B16

 90 B16

 91 B2 

 92 B2 

 95 B2 

 96 B2 

100 B17

102 B2 

103 B2 

*Compound 50 was obtained as a side-product during the reaction.

Analytical Part LCMS (Liquid Chromatography/Mass Spectrometry) LCMSGeneral Procedure

The High Performance Liquid Chromatography (HPLC) measurement wasperformed using a LC pump, a diode-array (DAD) or a UV detector and acolumn as specified in the respective methods. If necessary, additionaldetectors were included (see table of methods below).

Flow from the column was brought to the Mass Spectrometer (MS) which wasconfigured with an atmospheric pressure ion source. It is within theknowledge of the skilled person to set the tune parameters (e.g.scanning range, dwell time . . . ) in order to obtain ions allowing theidentification of the compound's nominal monoisotopic molecular weight(MW). Data acquisition was performed with appropriate software.Compounds are described by their experimental retention times (R_(t))and ions. If not specified differently in the table of data, thereported molecular ion corresponds to the [M+H]⁺ (protonated molecule)and/or [M−H]⁻ (deprotonated molecule). For molecules with multipleisotopic patterns (e.g. Br, Cl), the reported value is the one obtainedfor the lowest isotope mass. All results were obtained with experimentaluncertainties that are commonly associated with the method used.

Hereinafter, “SQD” means Single Quadrupole Detector, “MSD” MassSelective Detector, “RT” room temperature, “BEH” bridgedethylsiloxane/silica hybrid, “DAD” Diode Array Detector, “HSS” HighStrength silica, “Q-Tof” Quadrupole Time-of-flight mass spectrometers,“CLND”, ChemiLuminescent Nitrogen Detector, “ELSD” Evaporative LightScanning Detector.

TABLE 2 LCMS Method codes (Flow expressed in mL/min; column temperature(T) in ° C.; Run time in minutes) Method Flow Run code Instrument ColumnMobile phase Gradient Col T time 1 Waters: Waters: A: 10 mM From 95% Ato 0.8 3 Acquity ® HSS T3 CH₃COONH₄ in 0% A in 2.5 min, UPLC ®- (1.8 μm,95% H₂O + 5% to 5% A in DAD 2.1 * 100 mm) CH₃CN 0.5 min and SQD B: CH₃CN55 2 Waters: Waters: A: 10 mM From 100% A to 0.8 3.5 Acquity ® HSS T3CH₃COONH₄ in 5% A in 2.10 min, UPLC ®- (1.8 μm, 95% H₂O + 5% to 0% A inDAD 2.1 * 100 mm) CH₃CN 0.90 min, to 5% A and SQD B: CH₃CN in 0.5 min 553 Waters: Waters: A: 25 mM From 100% A to 1.6 11 Alliance ®- XterraCH₃COONH₄ in 1% A, 49% B and DAD- MS C18 95% H₂O + 5% 50% C in 6.5 min,ZQ and (3.5 μm, CH₃CN to 1% A and 99% ELSD 4.6 * B: CH₃CN B in 0.5 min,to 40 2000 100 mm) C: CH₃OH 100% D in 1 min Alltech D: (40% CH₃CN heldfor 1.0 min and 40% CH₃OH to 100% A in 0.5 min and 20% H₂O with and heldfor 0.25% CH₃COOH 1.5 min. 4 Waters: Waters: A: 10 mM From 95% A to 0.82 Acquity ® BEH CH₃COONH₄ in 5% A in 1.3 min, UPLC ®- C18 95% H₂O + 5%held for 0.7 min. DAD (1.7 μm, CH₃CN and SQD 2.1 * 50 mm) B: CH₃CN 55 5Agilent YMC- A: 0.1% HCOOH From 95% A to 2.6 6.0 1100- pack in H₂O 5% Ain 4.8 min, DAD- ODS-AQ B: CH₃CN held for 1.0 min, 35 MSD C18 (50 × to95% A in 0.2 min. G1956A 4.6 mm, 3 μm) 6 Waters: Waters: A: 0.1% HCOOH +From 95% A to 0.8 3 Acquity ® BEH 5% CH₃OH in H₂O 0% A in 2.5 min,UPLC ®- C18 B: CH₃CN to 5% A in 55 DAD (1.7 μm, 0.5 min. and SQD 2.1 *50 mm) 7 Waters: Waters: A: 10 mM From 100% A to 0.7 3.5 Acquity ® HSST3 CH₃COONH₄ in 5% A in 2.10 min, UPLC ®- (1.8 μm, 95% H₂O + 5% to 0% Ain DAD 2.1 * 100 mm) CH₃CN 0.90 min, to 5% A and SQD B: CH₃CN in 0.5 min55

Melting Points

For compounds 9, 13, 14, 19, 26, 28 and 29 melting points (m.p.) weredetermined with a DSC823e (Mettler-Toledo). The m.p. of compounds 13,19, 26, 28 and 29 were measured with a temperature gradient of 10°C./min. The m.p. of compound 14 was measured with a temperature gradientof 30° C./min.

For compounds 30, 33, 40, 43, 44, 48, 51, 52 and 53 m.p. were determinedin open capillary tubes on a Mettler FP62 apparatus. M.p. were measuredwith a temperature ranging from 50° C. to 300° C., using a gradient of10° C./minute. The m.p. value was read from a digital display.

The results of the analytical measurements are shown in table 3.

TABLE 3 Retention time (R_(t)) in min., [M + H]⁺ peak (protonatedmolecule), LCMS method and m.p. (melting point in ° C.) (n.d. means notdetermined). Co. LCMS m.p. No. R_(t) [M + H]⁺ Method (° C.) 1 2.79 513 5n.d. 2 0.65 462 4 n.d. 3 0.64 462 4 n.d. 4 0.65 462 4 n.d. 5 0.77 461 4n.d. 6 1.53 461 2 n.d. 7 1.53 461 2 n.d. 8 0.70 458 4 n.d. 9 1.62 457 2170 38 0.80 432 4 n.d. 39 1.89 433 1 n.d. 10 0.87 433 4 n.d. 11 1.83 4691 n.d. 12 0.96 418 4 n.d. 13 0.96 467 4 159 14 5.37 424 3 147 15 1.79497 6 n.d. 16 0.87 463 4 n.d. 17 0.95 473 4 n.d. 18 0.96 473 4 n.d. 190.89 463 4 144 20 1.87 484 2 n.d. 21 1.85 484 2 n.d. 22 5.09 406 3 n.d.23 1.61 486 2 n.d. 24 5.35 437 3 n.d. 25 0.76 435 4 n.d. 26 1.01 457 4164 27 0.97 507 4 n.d. 28 0.91 423 4 162 29 0.89 437 4 110 30 2.36 444 5122 31 n.d. n.d. — n.d. 32 0.97 440 4 n.d. 33 2.52 473 5 149 34 1.90 4772 n.d. 35 1.89 477 2 n.d. 36 1.89 477 2 n.d. 37 1.90 477 2 n.d. 41 0.92451 4 n.d. 42 1.91 449 1 n.d. 43 n.d. n.d. — 138 44 2.21 445 5 128 451.04 477 4 n.d. 46 1.91 477 2 n.d. 47 1.90 477 2 n.d. 48 2.68 487 5 12249 2.66 487 5 n.d. 50 2.09 447 5 n.d. 51 n.d. n.d. — 212 52 n.d. n.d. —223 40 2.70 487 5 102 53 2.94 513 5 197 54 0.91 409 4 n.d. 55 0.94 423 4n.d. 56 0.94 427 2 232 57 1.66 437 2 n.d. 58 1.64 437 2 n.d. 59 2.30 4415 n.d. 60 1.63 441 2 234 61 1.63 441 2 231 62 1.67 441 2 n.d. 63 1.74441 2 n.d. 64 1.60 443 2 211 65 2.43 455 5 n.d. 66 5.91 455 3 n.d. 671.68 457 2 200 68 1.68 457 2 204 69 1.74 457 2 n.d. 70 1.74 457 2 n.d.71 1.72 457 2 225 72 1.72 457 2 215 73 1.75 457 2 187 74 1.87 457 2 20275 1.73 459 2 n.d. 76 1.72 459 2 n.d. 77 1.68 467 2 n.d. 78 1.82 471 2n.d. 79 1.79 471 2 n.d. 80 1.78 471 2 n.d. 81 1.68 473 2 n.d. 82 1.68473 2 n.d. 83 1.79 473 2 n.d. 84 1.02 475 4 222 85 1.02 475 4 226 861.84 487 2 n.d. 87 1.82 487 2 n.d. 88 2.06 511 2 n.d. 89 1.73 489 2 23090 1.71 489 2 n.d. 91 1.04 489 4 n.d. 92 1.03 489 4 n.d. 93 1.82 491 2n.d. 94 1.88 443 7 n.d. 95 1.9 455 7 n.d. 96 1.92 455 7 201 97 1.05 4574 227 98 0.8    452.8 4 n.d. 99 1.63 425 2 n.d. 100 1.72 439 2 n.d. 1015.46 458 3 140 102 1.91 477 2 n.d. 103 1.91 477 2 n.d. 104 1.02 483 4n.d.

NMR

For a number of compounds, ¹H NMR spectra were recorded on a BrukerAvance III with a 300 MHz Ultrashield magnet, on a Bruker DPX-400spectrometer operating at 400 MHz, on a Bruker DPX-360 operating at 360MHz, or on a Bruker Avance 600 spectrometer operating at 600 MHz, usingCHLOROFORM-d (deuterated chloroform, CDCl₃) or DMSO-d₆ (deuterated DMSO,dimethyl-d6 sulfoxide) as solvent. Chemical shifts (δ) are reported inparts per million (ppm) relative to tetramethylsilane (TMS), which wasused as internal standard.

TABLE 4 ¹H NMR results Co. No. ¹H NMR result 3 (360 MHz, DMSO-d₆) δ ppm1.19 (d, J = 6.6 Hz, 3 H), 1.77-1.93 (m, 1 H), 2.15 (s, 4 H), 2.87 (ddd,J = 17.2, 11.5, 6.0 Hz, 1 H), 2.96-3.24 (m, 2 H), 3.84-4.04 (m, 3 H),4.40 (dd, J = 12.3, 5.3 Hz, 1 H), 4.53 (d, J = 15.7 Hz, 1 H), 4.60 (dd,J = 13.9, 2.9 Hz, 1 H), 5.22 (d, J = 15.7 Hz, 1 H), 7.13 (d, J = 7.7 Hz,1 H), 7.39-7.46 (m, 1 H), 7.81 (d, J = 7.7 Hz, 1 H), 8.28 (d, J = 1.5Hz, 1 H) 4 (360 MHz, DMSO-d₆) δ ppm 1.16 (d, J = 6.6 Hz, 3 H), 1.75-1.95(m, 1 H), 2.10-2.26 (m, 4 H), 2.87 (ddd, J = 16.8, 11.0, 5.9 Hz, 1 H),3.03 (dt, J = 16.6, 4.8 Hz, 1 H), 3.12-3.25 (m, 1 H), 3.89 (dd, J =13.9, 4.0 Hz, 1 H), 3.93-4.13 (m, 2 H), 4.39 (dd, J = 12.4, 5.9 Hz, 1H), 4.53-4.68 (m, 2 H), 5.15 (d, J = 15.7 Hz, 1 H), 7.03-7.24 (m, 1 H),7.43 (s, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 8.28 (d, J = 1.1 Hz, 1 H) 6(360 MHz, CHLOROFORM-d) δ ppm 1.26 (d, J = 6.8 Hz, 3 H), 2.08 (qd, J =12.4, 5.6 Hz, 1 H), 2.28 (s, 3 H), 2.38 (d, J = 13.9 Hz, 1 H), 2.55-2.67(m, 1 H), 2.73 (dd, J = 16.1, 11.7 Hz, 1 H), 3.21 (dd, J = 16.1, 4.7 Hz,1 H), 3.66 (dd, J = 14.1, 4.1 Hz, 1 H), 3.81-3.91 (m, 1 H), 4.01 (d, J =15.0 Hz, 1 H), 4.11 (td, J = 12.5, 4.7 Hz, 1 H), 4.42 (dd, J = 13.4, 5.6Hz, 1 H), 4.78 (d, J = 14.1 Hz, 1 H), 5.12 (d, J = 15.0 Hz, 1 H), 7.14(s, 1 H), 7.21-7.31 (m, 1 H), 7.47 (d, J = 8.1 Hz, 1 H), 7.50 (s, 1 H),8.23 (s, 1 H) 7 (360 MHz, CHLOROFORM-d) δ ppm 1.26 (d, J = 6.6 Hz, 3 H),2.10 (dtd, J = 13.7, 11.7, 11.7, 5.6 Hz, 1 H), 2.29 (s, 3 H), 2.33-2.42(m, 1 H), 2.56-2.69 (m, 1 H), 2.81 (dd, J = 16.5, 11.0 Hz, 1 H), 3.26(ddd, J = 16.5, 5.3, 1.7 Hz, 1 H), 3.70 (dd, J = 14.2, 4.1 Hz, 1 H),3.91 (qdd, J = 6.6, 6.6, 6.6, 4.2, 2.0 Hz, 1 H), 4.06 (d, J = 15.0 Hz, 1H), 4.10 (td, J = 12.4, 4.8 Hz, 1 H), 4.42 (ddd, J = 13.1, 5.5, 2.7 Hz,1 H), 4.80 (dd, J = 14.1, 2.3 Hz, 1 H), 5.04 (d, J = 15.1 Hz, 1 H), 7.14(s, 1 H), 7.27 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.50 (s,1 H), 8.24 (s, 1 H) 8 (400 MHz, DMSO-d₆) δ ppm 1.23 (d, J = 6.9 Hz, 3H), 2.15 (s, 3 H), 3.81-3.98 (m, 1 H), 4.17 (br. s., 1 H), 4.59 (dd, J =14.1, 2.8 Hz, 1 H), 5.08 (d, J = 15.7 Hz, 1 H), 5.59 (d, J = 15.7 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1 H), 7.42 (s, 1 H), 7.64 (d, J = 10.1 Hz, 1H), 7.80 (d, J = 7.7 Hz, 1 H), 8.00 (d, J = 9.7 Hz, 1 H), 8.27 (s, 1 H),9.19 (s, 1 H) 9 (360 MHz, DMSO-d₆) δ ppm 1.12 (d, J = 6.6 Hz, 3 H),2.11-2.18 (m, 3 H), 3.76 (dd, J = 14.3, 4.0 Hz, 1 H), 4.07 (ddd, J =6.5, 4.1, 2.2 Hz, 1 H), 4.59 (dd, J = 13.9, 2.2 Hz, 1 H), 4.67 (d, J =15.0 Hz, 1 H), 5.17 (d, J = 15.0 Hz, 1 H), 7.11-7.18 (m, 2 H), 7.39-7.44(m, 1 H), 7.81 (d, J = 7.7 Hz, 1 H), 8.26 (d, J = 1.5 Hz, 1 H), 8.31 (s,1 H), 8.39-8.45 (m, 1 H), 8.90 (d, J = 7.3 Hz, 1 H) 38 (400 MHz,CHLOROFORM-d) δ ppm 1.28 (t, J = 6.3 Hz, 3 H), 2.29 (d, J = 1.2 Hz, 3H), 2.90 (t, J = 5.9 Hz, 1 H), 2.99 (q, J = 6.1 Hz, 1 H), 3.67-3.78 (m,1 H), 3.79-3.96 (m, 2 H), 3.98-4.14 (m, 1 H), 4.21 (dd, J = 14.1, 4.0Hz, 1 H), 4.68 (m, J = 3.2 Hz, 1 H), 4.65-4.76 (m, 1 H), 5.10 (dd, J =15.9, 10.3 Hz, 1 H), 7.08-7.25 (m, 6 H), 7.26 (s, 2 H), 7.44 (d, J = 7.7Hz, 1 H), 8.24 (d, J = 1.2 Hz, 1 H) 39 (360 MHz, CHLOROFORM-d) δ ppm1.22 (d, J = 6.6 Hz, 3 H), 1.33 (s, 6 H), 1.76-1.85 (m, 2 H), 2.29 (s, 3H), 2.76 (t, J = 6.8 Hz, 2 H), 3.62-3.70 (m, 1 H), 3.77-3.89 (m, 1 H),3.98 (d, J = 14.6 Hz, 1 H), 4.76 (dd, J = 13.9, 2.2 Hz, 1 H), 5.31 (d, J= 14.6 Hz, 1 H), 6.76 (d, J = 9.1 Hz, 1 H), 6.99-7.06 (m, 2 H), 7.14 (s,1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 8.23 (d, J =1.5 Hz, 1 H) 10 (360 MHz, CHLOROFORM-d) δ ppm 1.27 (d, J = 6.6 Hz, 3 H),2.29 (s, 3 H), 3.80 (dd, J = 14.1, 4.2 Hz, 1 H), 3.88-4.00 (m, 1 H),4.37 (d, J = 15.4 Hz, 1 H), 4.77 (dd, J = 13.9, 2.6 Hz, 1 H), 5.34 (d, J= 15.4 Hz, 1 H), 7.01 (s, 1 H), 7.14 (s, 1 H), 7.20 (d, J = 1.5 Hz, 1H), 7.31 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 8.25 (d, J =1.1 Hz, 1 H) 11 (360 MHz, CHLOROFORM-d) δ ppm 1.25 (d, J = 6.6 Hz, 3 H),2.24-2.33 (m, 3 H), 3.25 (t, J = 8.6 Hz, 2 H), 3.71-3.84 (m, 1 H),3.95-4.06 (m, 1 H), 4.16 (d, J = 14.6 Hz, 1 H), 4.62 (td, J = 8.8, 2.9Hz, 2 H), 4.78 (dd, J = 13.9, 2.2 Hz, 1 H), 5.11 (d, J = 15.0 Hz, 1 H),7.14 (s, 1 H), 7.25-7.31 (m, 3 H), 7.46 (d, J = 7.7 Hz, 1 H), 8.23 (d, J= 1.1 Hz, 1 H) 13 (360 MHz, DMSO-d₆) δ ppm 1.12 (d, J = 6.6 Hz, 3 H),2.15 (s, 3 H), 3.95 (dd, J = 14.1, 3.8 Hz, 1 H), 4.03-4.16 (m, 1 H),4.63 (dd, J = 14.1, 2.4 Hz, 1 H), 4.75 (d, J = 16.1 Hz, 1 H), 5.07 (d, J= 16.1 Hz, 1 H), 6.96 (s, 1 H), 7.13 (d, J = 7.7 Hz, 1 H), 7.38-7.49 (m,2 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.77-7.90 (m, 2 H), 8.28 (d, J = 1.1Hz, 1 H) 14 (360 MHz, CHLOROFORM-d) δ ppm 1.31 (d, J = 6.6 Hz, 3 H),2.28 (s, 3 H), 3.69-3.81 (m, 1 H), 3.99-4.11 (m, 1 H), 4.62 (d, J = 15.0Hz, 1 H), 4.75 (dd, J = 14.3, 2.9 Hz, 1 H), 5.57 (d, J = 15.4 Hz, 1 H),7.14 (s, 1 H), 7.34 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H),7.55 (s, 2 H), 7.87 (s, 1 H), 8.24 (s, 1 H) 15 (600 MHz, CHLOROFORM-d) δppm 1.19 (d, J = 6.7 Hz, 2 H), 1.28-1.34 (m, 6 H), 1.74-1.83 (m, 3 H),1.84-1.95 (m, 4 H), 2.28 (d, J = 9.2 Hz, 4 H), 2.72 (dd, J = 5.7, 2.6Hz, 1 H), 2.77-2.91 (m, 2 H), 3.16 (d, J = 14.2 Hz, 1 H), 3.24-3.32 (m,1 H), 3.67 (dd, J = 14.2, 4.2 Hz, 1 H), 3.96 (dd, J = 14.1, 4.0 Hz, 1H), 4.20-4.36 (m, 3 H), 4.25-4.29 (m, 1 H), 4.78 (dd, J = 14.2, 2.1 Hz,1 H), 4.89 (dd, J = 14.1, 1.9 Hz, 1 H), 6.61-6.72 (m, 1 H), 7.11-7.29(m, 7 H), 7.12-7.28 (m, 1 H), 7.12-7.19 (m, 1 H), 7.45 (dd, J = 17.2,7.7 Hz, 1 H), 8.13-8.29 (m, 1 H) - mixture of diastereoisomers 45/55 17(360 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J = 6.6 Hz, 3 H), 1.53 (s, 3 H),2.25-2.32 (m, 3 H), 3.01 (d, J = 13.9 Hz, 1 H), 3.86 (dd, J = 14.3, 4.0Hz, 1 H), 4.42 (dt, J = 4.4, 2.2 Hz, 1 H), 4.57 (d, J = 14.3 Hz, 1 H),4.88 (dd, J = 14.3, 2.2 Hz, 1 H), 5.17 (d, J = 5.1 Hz, 2 H), 7.16 (t, J= 1.1 Hz, 1 H), 7.30 (d, J = 7.7 Hz, 1 H), 7.39 (d, J = 7.7 Hz, 1 H),7.48 (d, J = 7.7 Hz, 1 H), 7.54 (s, 1 H), 7.62 (d, J = 8.1 Hz, 1 H),8.26 (d, J = 1.5 Hz, 1 H) 18 (360 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J =7.0 Hz, 3 H), 1.55 (s, 3 H), 2.27 (d, J = 1.1 Hz, 3 H), 3.28 (dd, J =13.9, 4.0 Hz, 1 H), 3.35 (d, J = 14.6 Hz, 1 H), 4.29 (qdd, J = 6.7, 6.7,6.7, 4.4, 2.2 Hz, 1 H), 4.63 (d, J = 14.3 Hz, 1 H), 4.68 (dd, J = 13.9,2.2 Hz, 1 H), 5.15 (d, J = 3.3 Hz, 2 H), 7.08 (t, J = 1.1 Hz, 1 H), 7.14(d, J = 7.7 Hz, 1 H), 7.29 (d, J = 8.1 Hz, 1 H), 7.37 (d, J = 7.7 Hz, 1H), 7.53 (d, J = 7.0 Hz, 1 H), 7.60 (s, 1 H), 8.18 (d, J = 1.1 Hz, 1 H)19 (360 MHz, CHLOROFORM-d) δ ppm 1.26 (d, J = 7.0 Hz, 9 H), 2.29 (s, 3H), 2.97 (quin, J = 7.0 Hz, 1 H), 3.71 (dd, J = 14.3, 4.0 Hz, 1 H),3.92-4.02 (m, 1 H), 4.30 (d, J = 15.7 Hz, 1 H), 4.77-4.86 (m, 2 H),4.90-5.02 (m, 1 H), 5.20 (d, J = 15.7 Hz, 1 H), 6.18 (s, 1 H), 7.14 (s,1 H), 7.29 (s, 1 H), 7.46 (d, J = 7.7 Hz, 1 H), 8.25 (d, J = 1.1 Hz, 1H) 20 (400 MHz, DMSO-d₆) δ ppm 1.14 (d, J = 6.9 Hz, 3 H), 2.13-2.19 (m,3 H), 3.93 (dd, J = 14.1, 4.0 Hz, 1 H), 4.09-4.17 (m, 1 H), 4.61 (dd, J= 14.1, 2.8 Hz, 1 H), 4.97 (d, J = 16.1 Hz, 1 H), 5.44 (d, J = 15.7 Hz,1 H), 7.13 (d, J = 7.7 Hz, 1 H), 7.42 (s, 1 H), 7.77-7.83 (m, 2 H), 8.22(d, J = 8.9 Hz, 1 H), 8.27 (d, J = 1.2 Hz, 1 H), 8.53 (d, J = 1.6 Hz, 1H) 21 (400 MHz, DMSO-d₆) δ ppm 1.15 (d, J = 6.9 Hz, 3 H), 2.15 (d, J =0.8 Hz, 3 H), 3.93 (dd, J = 14.1, 4.0 Hz, 1 H), 4.10-4.17 (m, 1 H), 4.61(dd, J = 13.9, 3.0 Hz, 1 H), 4.99 (d, J = 16.1 Hz, 1 H), 5.47 (d, J =16.1 Hz, 1 H), 7.13 (d, J = 7.7 Hz, 1 H), 7.42 (s, 1 H), 7.55 (dd, J =8.1, 7.7 Hz, 1 H), 7.81 (d, J = 8.1 Hz, 1 H), 7.93 (dd, J = 7.3, 0.8 Hz,1 H), 8.27 (d, J = 0.8 Hz, 1 H), 8.33 (dd, J = 8.1, 0.8 Hz, 1 H) 22 (360MHz, DMSO-d₆) δ ppm 1.12 (d, J = 7.0 Hz, 3 H), 2.15 (s, 3 H), 3.92 (dd,J = 13.9, 4.0 Hz, 1 H), 4.07-4.18 (m, 1 H), 4.63 (dd, J = 13.9, 2.9 Hz,1 H), 5.00 (d, J = 16.1 Hz, 1 H), 5.47 (d, J = 16.1 Hz, 1 H), 7.14 (d, J= 8.1 Hz, 1 H), 7.43 (s, 1 H), 7.56 (t, J = 7.5 Hz, 1 H), 7.62-7.69 (m,1 H), 7.82 (d, J = 7.7 Hz, 1 H), 8.21-8.30 (m, 3 H) 24 (360 MHz,DMSO-d₆) δ ppm 1.09 (d, J = 7.0 Hz, 3 H), 2.15 (s, 3 H), 3.74 (dd, J =14.1, 4.2 Hz, 1 H), 3.95-4.09 (m, 4 H), 4.57 (dd, J = 13.9, 2.6 Hz, 1H), 4.74 (d, J = 15.0 Hz, 1 H), 5.25 (d, J = 15.0 Hz, 1 H), 7.17 (d, J =7.7 Hz, 1 H), 7.38-7.46 (m, 2 H), 7.70 (d, J = 9.1 Hz, 1 H), 7.81 (d, J= 7.7 Hz, 1 H), 7.86-7.91 (m, 1 H), 8.26 (s, 1 H) 25 (360 MHz,CHLOROFORM-d) δ ppm 1.23 (d, J = 6.6 Hz, 3 H), 2.25-2.32 (m, 6 H), 3.76(dd, J = 14.1, 4.2 Hz, 1 H), 3.97-4.05 (m, 1 H), 4.25 (d, J = 15.0 Hz, 1H), 4.53-4.65 (m, 2 H), 4.74 (dd, J = 13.9, 2.6 Hz, 1 H), 5.13 (d, J =14.6 Hz, 1 H), 6.11 (s, 1 H), 7.14 (s, 1 H), 7.29 (s, 1 H), 7.46 (d, J =7.7 Hz, 1 H), 8.23 (d, J = 1.5 Hz, 1 H) 26 (360 MHz, CHLOROFORM-d) δ ppm1.31 (d, J = 6.6 Hz, 3 H), 2.29 (s, 3 H), 3.89 (dd, J = 14.1, 4.2 Hz, 1H), 4.03-4.10 (m, 1 H), 4.52 (d, J = 15.7 Hz, 1 H), 4.78 (dd, J = 14.3,2.9 Hz, 1 H), 5.27-5.35 (m, 1 H), 6.85 (s, 1 H), 7.14 (s, 1 H), 7.31 (d,J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 7.53-7.59 (m, 2 H), 7.86(s, 1 H), 8.25 (d, J = 1.5 Hz, 1 H) 28 (360 MHz, CHLOROFORM-d) δ ppm1.26 (d, J = 6.6 Hz, 3 H), 2.29 (d, J = 0.7 Hz, 3 H), 3.78 (dd, J =14.1, 4.2 Hz, 1 H), 3.84-3.92 (m, 1 H), 4.27 (d, J = 15.4 Hz, 1 H), 4.78(dd, J = 14.3, 2.6 Hz, 1 H), 5.17 (d, J = 15.0 Hz, 1 H), 7.14 (s, 1 H),7.31 (d, J = 7.7 Hz, 1 H), 7.43 (s, 2 H), 7.48 (d, J = 7.7 Hz, 1 H),8.25 (d, J = 1.5 Hz, 1 H) 29 (360 MHz, CHLOROFORM-d) δ ppm 1.22 (d, J =7.0 Hz, 3 H), 2.29 (s, 3 H), 3.55 (q, J = 10.5 Hz, 2 H), 3.72 (dd, J =14.1, 4.2 Hz, 1 H), 3.83-3.91 (m, 1 H), 4.23 (d, J = 15.0 Hz, 1 H), 4.78(dd, J = 14.1, 2.4 Hz, 1 H), 5.16 (d, J = 15.0 Hz, 1 H), 6.99 (s, 1 H),7.14 (s, 1 H), 7.18-7.21 (m, 1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.47 (d, J= 7.7 Hz, 1 H), 8.24 (d, J = 1.5 Hz, 1 H) 30 (300 MHz, DMSO-d₆) δ ppm0.33 (td, J = 7.4, 4.3 Hz, 1 H), 0.52 (d, J = 3.3 Hz, 1 H), 0.92 (d, J =6.5 Hz, 3 H), 1.39 (br. s., 2 H), 2.01 (s, 3 H), 2.18 (s, 3 H), 2.87(br. s., 2 H), 3.18 (dd, J = 8.9, 4.2 Hz, 2 H), 3.69-3.79 (m, 2 H), 4.15(d, J = 15.0 Hz, 1 H), 4.34-4.53 (m, 1 H), 4.83 (d, J = 14.8 Hz, 1 H),6.58-6.83 (m, 2 H), 6.90 (d, J = 7.7 Hz, 1 H), 7.07 (d, J = 7.7 Hz, 1H), 7.72 (t, J = 1.4 Hz, 1 H), 7.95 (d, J = 7.7 Hz, 1 H), 9.33-9.49 (m,1 H) 32 (360 MHz, DMSO-d₆) δ ppm 1.11 (d, J = 6.6 Hz, 3 H), 2.33 (s, 3H), 3.91 (dd, J = 14.1, 4.2 Hz, 1 H), 3.97 (d, J = 5.5 Hz, 1 H), 4.46(d, J = 15.0 Hz, 1 H), 4.60 (dd, J = 13.7, 1.6 Hz, 1 H), 5.01 (d, J =15.4 Hz, 1 H), 6.93 (dd, J = 8.2, 2.4 Hz, 1 H), 6.97-7.04 (m, 2 H), 7.06(s, 1 H), 7.10-7.19 (m, 2 H), 7.21 (d, J = 7.7 Hz, 1 H), 7.34-7.44 (m, 3H), 7.86 (s, 1 H), 8.09 (d, J = 7.7 Hz, 1 H), 9.50 (s, 1 H) 33 (300 MHz,DMSO-d₆) δ ppm 0.65-0.73 (m, 2 H), 0.78-0.88 (m, 2 H), 1.14 (d, J = 6.5Hz, 3 H), 2.35 (s, 3 H), 3.91-4.09 (m, 3 H), 4.53 (d, J = 15.4 Hz, 1 H),4.57-4.67 (m, 1 H), 5.08 (d, J = 15.3 Hz, 1 H), 7.25 (d, J = 7.7 Hz, 1H), 7.28-7.39 (m, 3 H), 7.87 (s, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 9.51(s, 1 H) 34 (600 MHz, CHLOROFORM-d) δ ppm 1.26 (d, J = 6.7 Hz, 3 H),1.77 (qd, J = 12.5, 5.6 Hz, 1 H), 2.21-2.27 (m, 1 H), 2.29 (d, J = 1.1Hz, 3 H), 2.42-2.51 (m, 1 H), 2.62 (dd, J = 14.7, 12.6 Hz, 1 H),2.73-2.81 (m, 1 H), 2.87 (dd, J = 16.1, 5.3 Hz, 1 H), 2.88-2.93 (m, 1H), 3.78 (dd, J = 14.1, 4.1 Hz, 1 H), 3.92-3.98 (m, 1 H), 4.26 (d, J =15.3 Hz, 1 H), 4.76 (dt, J = 14.1, 2.3 Hz, 1 H), 5.34 (d, J = 15.3 Hz, 1H), 6.74 (s, 1 H), 7.14 (s, 1 H), 7.30 (d, J = 8.4 Hz, 1 H), 7.46 (d, J= 7.6 Hz, 1 H), 8.24 (d, J = 1.4 Hz, 1 H) 36 (360 MHz, CHLOROFORM-d) δppm 1.22 (d, J = 6.6 Hz, 3 H), 1.73-1.84 (m, 1 H), 2.22-2.31 (m, 4 H),2.38-2.53 (m, 2 H), 2.78-2.91 (m, 2 H), 2.93-3.02 (m, 1 H), 3.70 (dd, J= 14.3, 4.0 Hz, 1 H), 3.78-3.86 (m, 1 H), 4.10 (d, J = 15.4 Hz, 1 H),4.80 (dd, J = 14.3, 2.2 Hz, 1 H), 5.22 (d, J = 15.0 Hz, 1 H), 7.03 (s, 1H), 7.15 (t, J = 1.1 Hz, 1 H), 7.32 (d, J = 7.7 Hz, 1 H), 7.48 (d, J =7.7 Hz, 1 H), 8.24 (d, J = 1.5 Hz, 1 H) 37 (360 MHz, CHLOROFORM-d) δ ppm1.20 (d, J = 7.0 Hz, 3 H), 1.72-1.85 (m, 1 H), 2.20-2.33 (m, 4 H),2.39-2.60 (m, 2 H), 2.76-2.90 (m, 2 H), 2.90-3.02 (m, 1 H), 3.75 (dd, J= 14.1, 4.2 Hz, 1 H), 3.83-3.94 (m, 1 H), 4.21 (d, J = 15.4 Hz, 1 H),4.77-4.87 (m, 1 H), 5.08 (d, J = 15.4 Hz, 1 H), 7.00 (s, 1 H), 7.14 (s,1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.7 Hz, 1 H), 8.24 (d, J =1.5 Hz, 1 H) 41 (360 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J = 6.6 Hz, 3 H),2.29 (s, 3 H), 2.91-3.10 (m, 2 H), 3.13-3.25 (m, 1 H), 3.50-3.62 (m, 4H), 4.22-4.33 (m, 1 H), 4.64-4.71 (m, 1 H), 6.94 (s, 1 H), 7.00 (s, 1H), 7.13 (s, 1 H), 7.24 (d, J = 7.7 Hz, 1 H), 7.45 (d, J = 7.7 Hz, 1 H),8.23 (s, 1 H) 42 (360 MHz, DMSO-d₆) δ ppm 1.08 (d, J = 6.6 Hz, 3 H),1.26 (d, J = 5.9 Hz, 6 H), 2.15 (s, 3 H), 3.06 (t, J = 8.8 Hz, 2 H),3.74-3.85 (m, 1 H), 3.85-4.00 (m, 1 H), 4.24 (d, J = 14.6 Hz, 1 H),4.48-4.70 (m, 4 H), 4.84 (d, J = 15.0 Hz, 1 H), 6.48 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1 H), 7.10 (d, J = 7.7 Hz, 1 H), 7.42 (s, 1 H),7.81 (d, J = 8.1 Hz, 1 H), 8.23-8.33 (m, 1 H) 44 (300 MHz, DMSO-d₆) δppm 2.16 (s, 3 H), 3.17 (dd, J = 16.6, 6.7 Hz, 1 H), 3.51 (dd, J = 16.5,9.2 Hz, 1 H), 3.71-3.93 (m, 4 H), 4.07 (ddd, J = 14.2, 7.7, 4.4 Hz, 1H), 4.20-4.36 (m, 1 H), 5.13-5.28 (m, 1 H), 7.10 (d, J = 7.7 Hz, 2 H),7.17 (d, J = 7.7 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.39-7.44 (m, 1H), 7.79 (d, J = 7.8 Hz, 1 H), 8.26 (d, J = 1.0 Hz, 1 H) 46 (360 MHz,CHLOROFORM-d) δ ppm 1.21 (d, J = 6.6 Hz, 3 H), 1.70-1.79 (m, 1 H),2.15-2.26 (m, 1 H), 2.29 (s, 3 H), 2.43 (d, J = 17.9 Hz, 2 H), 2.72-2.91(m, 2 H), 3.07 (dd, J = 16.3, 5.3 Hz, 1 H), 3.64 (dd, J = 14.3, 4.4 Hz,1 H), 3.82 (ddd, J = 6.9, 4.5, 2.2 Hz, 1 H), 4.06 (d, J = 15.0 Hz, 1 H),4.76-4.86 (m, 1 H), 5.27 (d, J = 15.0 Hz, 1 H), 7.05 (s, 1 H), 7.15 (s,1 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.48 (d, J = 7.7 Hz, 1 H), 8.24 (s, 1H) 47 (360 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J = 7.0 Hz, 3 H), 1.72-1.81(m, 1 H), 2.15-2.26 (m, 1 H), 2.29 (s, 3 H), 2.42-2.60 (m, 2 H),2.69-2.91 (m, 2 H), 3.00-3.13 (m, 1 H), 3.68 (dd, J = 14.3, 4.4 Hz, 1H), 3.79-3.92 (m, 1 H), 4.23 (d, J = 15.0 Hz, 1 H), 4.82 (dd, J = 14.3,2.2 Hz, 1 H), 5.09 (d, J = 15.0 Hz, 1 H), 7.04 (s, 1 H), 7.14 (s, 1 H),7.30 (d, J = 7.7 Hz, 1 H), 7.44-7.51 (m, 1 H), 8.24 (s, 1 H) 48 (300MHz, DMSO-d6) δ ppm 0.64-0.72 (m, 2 H), 0.76-0.87 (m, 2 H), 1.18 (d, J =6.6 Hz, 3 H), 1.66 (d, J = 7.1 Hz, 3 H), 2.31 (s, 3 H), 3.62 (dd, J =13.9, 3.8 Hz, 1 H), 3.93-4.05 (m, 2 H), 4.60 (d, J = 14.0 Hz, 1 H), 5.69(q, J = 7.1 Hz, 1 H), 7.19 (d, J = 7.7 Hz, 1 H), 7.29-7.36 (m, 3 H),7.82 (s, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 9.41 (s, 1 H) 49 (300 MHz,DMSO-d₆) δ ppm 0.74 (d, J = 6.3 Hz, 5 H), 0.80-0.97 (m, 2 H), 1.76 (d, J= 7.1 Hz, 3 H), 2.38 (s, 3 H), 3.96 (dd, J = 14.0, 3.6 Hz, 1 H),4.02-4.14 (m, 1 H), 4.25-4.43 (m, 1 H), 4.68 (d, J = 13.7 Hz, 1 H),5.67-5.86 (m, 1 H), 7.29 (d, J = 7.7 Hz, 1 H), 7.35-7.49 (m, 3 H), 7.88(s, 1 H), 8.13 (d, J = 7.7 Hz, 1 H), 9.45 (s, 1 H) 51 (300 MHz, DMSO-d₆)δ ppm 1.12 (br. s., 2 H), 1.20 (br. s., 2 H), 1.61 (br. s., 2 H), 2.35(br. s., 2 H), 3.68 (d, J = 15.7 Hz, 2 H), 3.95 (br. s., 1 H), 4.64 (d,J = 15.3 Hz, 1 H), 5.67 (br. s., 1 H), 6.93 (br. s., 1 H), 7.10 (br. s.,1 H), 7.27 (br. s., 1 H), 7.88 (br. s., 1 H), 8.11 (br. s., 1 H), 9.52(br. s., 1 H), 10.28 (br. s., 1 H) 52 (400 MHz, DMSO-d6) δ ppm 0.64 (d,J = 6.5 Hz, 3 H), 1.61 (d, J = 6.9 Hz, 3 H), 2.34 (s, 3 H), 3.89 (dd, J= 13.9, 3.8 Hz, 1 H), 4.10-4.22 (m, 1 H), 4.61 (d, J = 12.5 Hz, 1 H),5.68 (q, J = 7.3 Hz, 1 H), 6.96 (dd, J = 8.5, 2.0 Hz, 1 H), 7.15 (d, J =2.0 Hz, 1 H), 7.22 (d, J = 7.7 Hz, 1 H), 7.26 (dd, J = 8.3, 1.0 Hz, 1H), 7.86 (s, 1 H), 8.11 (d, J = 7.7 Hz, 1 H), 9.52 (d, J = 1.6 Hz, 1 H),10.32 (s, 1 H) 56 (360 MHz, DMSO-d6) δ ppm 2.15 (d, J = 1.1 Hz, 3 H)3.69 (t, J = 5.9 Hz, 2 H) 4.21 (t, J = 5.5 Hz, 2 H) 4.81 (br. s, 2 H)7.18 (d, J = 7.7 Hz, 1 H) 7.41 (t, J = 1.1 Hz, 1 H) 7.50 (dd, J = 10.7,1.9 Hz, 1 H) 7.63 (d, J = 1.9 Hz, 1 H) 7.81 (d, J = 7.7 Hz, 1 H) 8.25(d, J = 1.4 Hz, 1 H) 8.29 (s, 1 H) 57 (360 MHz, CHLOROFORM-d) δ ppm 0.62(d, J = 6.6 Hz, 3 H) 1.72 (d, J = 6.9 Hz, 3 H) 2.29 (s, 3 H) 3.67 (dd, J= 14.1, 3.8 Hz, 1 H) 3.94-4.03 (m, 1 H) 4.87 (dd, J = 14.1, 1.7 Hz, 1 H)6.22 (dd, J = 13.9, 6.6 Hz, 1 H) 7.13 (br. s, 1 H) 7.29 (dd, J = 8.8,2.2 Hz, 1 H) 7.37-7.41 (m, 1 H) 7.42 (d, J = 8.8 Hz, 1 H) 7.50 (d, J =7.7 Hz, 1 H) 7.58 (d, J = 2.2 Hz, 1 H) 7.71 (br. s, 1 H) 8.24 (d, J =1.1 Hz, 1 H) 61 (360 MHz, CHLOROFORM-d) δ ppm 1.66 (d, J = 7.0 Hz, 3 H)2.28 (s, 3 H) 3.26 (ddd, J = 13.4, 6.3, 4.0 Hz, 1 H) 3.47-3.60 (m, 1 H)3.83-3.96 (m, 1 H) 4.41 (ddd, J = 14.3, 6.4, 3.8 Hz, 1 H) 6.23 (q, J =6.9 Hz, 1 H) 7.13 (br. s, 1 H) 7.33 (d, J = 8.6 Hz, 1 H) 7.40 (d, J =7.7 Hz, 1 H) 7.49 (d, J = 7.7 Hz, 1 H) 7.52 (d, J = 7.1 Hz, 1 H) 7.68(d, J = 1.3 Hz, 1 H) 8.21 (br. s, 1 H) 62 (360 MHz, DMSO-d6) δ ppm 1.12(d, J = 6.6 Hz, 3 H) 2.15 (d, J = 0.7 Hz, 3 H) 3.79 (dd, J = 14.1, 4.2Hz, 1 H) 4.00-4.08 (m, 1 H) 4.53 (d, J = 15.4 Hz, 1 H) 4.60 (dd, J =14.2, 2.2 Hz, 1 H) 5.09 (dd, J = 14.6, 0.73 Hz, 1 H) 7.18 (d, J = 7.7Hz, 1 H) 7.43 (t, J = 1.1 Hz, 1 H) 7.50 (dd, J = 10.7, 1.9 Hz, 1 H) 7.67(d, J = 1.8 Hz, 1 H) 7.83 (d, J = 7.7 Hz, 1 H) 8.27 (d, J = 1.4 Hz, 1 H)8.31 (br. s, 1 H) 65 (300 MHz, DMSO-d6) δ ppm 0.51 (d, J = 6.5 Hz, 3 H)1.70 (d, J = 6.9 Hz, 3 H) 2.16 (s, 3 H) 3.84 (dd, J = 13.8, 3.37 Hz, 1H) 4.19 (br. s., 1 H) 4.65 (d, J = 13.5 Hz, 1 H) 5.97 (q, J = 6.6 Hz, 1H) 7.24 (d, J = 7.7 Hz, 1 H) 7.42 (s, 1 H) 7.68 (d, J = 7.4 Hz, 1 H)7.83 (d, J = 7.8 Hz, 1 H) 7.88 (d, J = 9.4 Hz, 1 H) 8.27 (br. s., 1 H)8.29 (s, 1 H) 69 (360 MHz, CHLOROFORM-d) δ ppm 1.71 (d, J = 7.0 Hz, 3 H)2.28 (d, J = 0.9 Hz, 3 H) 3.24 (ddd, J = 13.4, 6.9, 3.9 Hz, 1 H) 3.55(ddd, J = 13.2, 8.7, 3.9 Hz, 1 H) 3.96 (ddd, J = 14.3, 8.5, 3.9 Hz, 1 H)4.35 (ddd, J = 10.7, 7.0, 3.5 Hz, 1 H) 6.31 (qd, J = 7.0, 1.2 Hz, 1 H)7.12 (br. s, 1 H) 7.41 (d, J = 7.7 Hz, 1 H) 7.49 (d, J = 7.7 Hz, 1 H)7.61 (d, J = 1.3 Hz, 2 H) 7.76 (d, J = 1.5 Hz, 1 H) 7.81 (s, 1 H) 8.21(d, J = 1.2 Hz, 1 H) 73 (400 MHz, CHLOROFORM-d) δ ppm 1.25 (d, J = 6.7Hz, 3 H) 2.28 (d, J = 0.9 Hz, 3 H) 3.65 (dd, J = 14.15, 4.15 Hz, 1 H)3.84-3.95 (m, 1 H) 4.40 (d, J = 15.16 Hz, 1 H) 4.76 (dd, J = 14.15, 2.45Hz, 1 H) 5.38 (dd, J = 15.16, 1.11 Hz, 1 H) 7.13 (t, J = 1.10 Hz, 1 H)7.36 (d, J = 7.69 Hz, 1 H) 7.48 (d, J = 7.69 Hz, 1 H) 7.61 (d, J = 1.28Hz, 2 H) 7.81 (s, 1 H) 7.97 (s, 1 H) 8.23 (d, J = 1.36 Hz, 1 H) 78 (360MHz, CHLOROFORM-d) δ ppm 0.58 (d, J = 6.6 Hz, 3 H) 1.74 (d, J = 7.3 Hz,3 H) 2.27 (s, 3 H) 3.68 (dd, J = 13.9, 3.3 Hz, 1 H) 3.95-4.03 (m, 1 H)4.86 (dd, J = 13.9, 1.5 Hz, 1 H) 6.30 (dd, J = 13.5, 6.2 Hz, 1 H) 7.13(s, 1 H) 7.37 (d, J = 7.7 Hz, 1 H) 7.48 (d, J = 7.7 Hz, 1 H) 7.52 (d, J= 8.8 Hz, 1 H) 7.73 (d, J = 8.4 Hz, 1 H) 7.78 (s, 1 H) 7.82 (s, 1 H)8.23 (s, 1 H) 89 (360 MHz, CHLOROFORM-d) δ ppm 0.62 (d, J = 6.6 Hz, 3 H)1.75 (d, J = 6.9 Hz, 3 H) 2.28 (s, 3 H) 3.69 (dd, J = 13.9, 3.7 Hz, 1 H)3.94-4.07 (m, 1 H) 4.87 (dd, J = 13.9, 1.5 Hz, 1 H) 6.26 (dd, J = 13.5,7.3 Hz, 1 H) 7.13 (br. s, 1 H) 7.35 (d, J = 9.9 Hz, 1 H) 7.39 (d, J =7.7 Hz, 1 H) 7.50 (d, J = 7.7 Hz, 1 H) 7.77 (d, J = 1.1 Hz, 1 H) 7.91(d, J = 6.6 Hz, 1 H) 8.20-8.28 (m, 1 H) 94 (360 MHz, CHLOROFORM-d) δ ppm2.28 (br. s, 3 H) 3.61 (t, J = 5.8 Hz, 2 H) 4.29 (t, J = 5.5 Hz, 2 H)4.84 (br. s, 2 H) 7.12 (s, 1 H) 7.38 (d, J = 7.7 Hz, 1 H) 7.47 (d, J =7.7 Hz, 1 H) 7.65 (s, 1 H) 7.72 (s, 1 H) 7.75 (s, 1 H) 8.22 (s, 1 H) 95(360 MHz, CHLOROFORM-d) δ ppm 1.30 (d, J = 6.7 Hz, 3 H) 1.74 (d, J = 7.1Hz, 3 H) 2.30 (d, J = 0.7 Hz, 3 H) 3.18 (dd, J = 14.1, 3.8 Hz, 1 H)3.63-3.89 (m, 1 H) 4.67 (dd, J = 14.0, 1.9 Hz, 1 H) 6.20 (qd, J = 6.8,1.2 Hz, 1 H) 7.12 (dd, J = 10.1, 1.9 Hz, 1 H) 7.15 (s, 1 H) 7.21 (d, J =1.9 Hz, 1 H) 7.36 (d, J = 7.7 Hz, 1 H) 7.51 (d, J = 7.7 Hz, 1 H) 7.76(d, J = 1.3 Hz, 1 H) 8.28 (s, 1 H) 96 (360 MHz, CHLOROFORM-d) δ ppm 0.64(d, J = 6.7 Hz, 3 H) 1.73 (d, J = 7.1 Hz, 3 H) 2.30 (d, J = 1.0 Hz, 3 H)3.68 (dd, J = 14.0, 3.8 Hz, 1 H) 3.95-4.04 (m, 1 H) 4.87 (dd, J = 14.0,1.9 Hz, 1 H) 6.21 (q, J = 6.8 Hz, 1 H) 7.11 (dd, J = 10.1, 1.9 Hz, 1 H)7.14 (s, 1 H) 7.39 (d, J = 7.7 Hz, 1 H) 7.39 (d, J = 1.8 Hz, 1 H) 7.51(d, J = 7.7 Hz, 1 H) 7.75 (d, J = 1.2 Hz, 1 H) 8.30 (s, 1 H) 97 (360MHz, CHLOROFORM-d) δ ppm 1.12 (d, J = 6.6 Hz, 3 H) 2.15 (s, 3 H) 3.80(dd, J = 14.1, 4.2 Hz, 1 H) 3.93-4.08 (m, 1 H) 4.51 (d, J = 15.3 Hz, 1H) 4.60 (dd, J = 14.1, 2.2 Hz, 1 H) 5.08 (d, J = 15.3 Hz, 1 H) 7.18 (d,J = 7.7 Hz, 1 H) 7.43 (br. s, 1 H) 7.83 (d, J = 7.7 Hz, 1 H) 7.99 (s, 1H) 8.06 (s, 1 H) 8.25 (s, 1 H) 8.27 (d, J = 1.1 Hz, 1 H)

SFC-MS

For SFC-MS, an analytical SFC system from Berger Instruments (Newark,Del., USA) was used comprising a dual pump control module (FCM-1200) fordelivery of CO₂ and modifier, a thermal control module for columnheating (TCM2100) with temperature control in the range 1-150° C. andcolumn selection valves (Valco, VICI, Houston, Tex., USA) for 6different columns. The photodiode array detector (Agilent 1100,Waldbronn, Germany) is equipped with a high-pressure flow cell (up to400 bar) and configured with a CTC LC Mini PAL auto sampler (LeapTechnologies, Carrboro, N.C., USA). A ZQ mass spectrometer (Waters,Milford, Mass., USA) with an orthogonal Z-electrospray interface iscoupled with the SFC-system. Instrument control, data collection andprocessing were performed with an integrated platform consisting of theSFC ProNTo software and Masslynx software.

Co. No. 6-7: SFC-MS was carried out on a OD-H column (250×4 6 mm)(Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Twomobile phases (mobile phase A: CO₂; mobile phase B: 2-propanolcontaining 0.2% 2-propylamine) were employed. 45% B was hold for 15 min.Column temperature was set at 30° C. Under these conditions, Co. No. 6had a shorter retention time (R_(t)) on the column than Co. No. 7. Themeasurement was compared against the mixture of compounds 6 and 7.

Co. No. 36-37: SFC-MS was carried out on a AD-H column (250×4 6 mm)(Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Twomobile phases (mobile phase A: CO₂; mobile phase B: ethanol containing0.2% 2-propylamine) were employed. 35% B was hold for 15 min. Columntemperature was set at 30° C. Under these conditions, Co. No. 36 had ashorter retention time (R_(t)) on the column than Co. No. 37. Themeasurement was compared against the mixture of compounds 36 and 37.

Co. No. 46-47: SFC-MS was carried out on a OJ-H column (250×4 6 mm)(Daicel Chemical Industries Ltd) with a flow rate of 3 ml/min. Twomobile phases (mobile phase A: CO₂; mobile phase B: methanol containing0.2% 2-propylamine) were employed. 10% B was hold for 15 min. Columntemperature was set at 30° C. Under these conditions, Co. No. 46 had ashorter retention time (R_(t)) on the column than Co. No. 47. Themeasurement was compared against the mixture of compounds 46 and 47.

Pharmacology A) Screening of the Compounds of the Invention forγ-Secretase-Modulating Activity

Screening was carried out using SKNBE2 human neuroblastoma cellscarrying the hAPP 695-wild type, grown in Dulbecco's Modified Eagle'sMedium/Nutrient mixture F-12 (DMEM/NUT-mix F-12) (HAM) provided byInvitrogen (cat no. 10371-029) containing 5% Serum/Fe supplemented with1% non-essential amino acids, 1-glutamine 2 mM, Hepes 15 mM, penicillin50 U/ml (units/ml) and streptomycin 50 μg/ml. Cells were grown to nearconfluency.

The screening was performed using a modification of the assay asdescribed in Citron et al (1997) Nature Medicine 3: 67. Briefly, cellswere plated in a 384-well plate at 10⁴ cells/well in Ultraculture(Lonza, BE12-725F) supplemented with 1% glutamine (Invitrogen,25030-024), 1% non-essential amino acid (NEAA), penicillin 50 U/ml enstreptomycin 50 μg/ml in the presence of test compound at different testconcentrations. The cell/compound mixture was incubated overnight at 37°C., 5% CO₂. The next day the media were assayed by two sandwichimmuno-assays, for Aβ42 and Aβtotal.

Aβtotal and Aβ42 concentrations were quantified in the cell supernatantusing the Aphalisa technology (Perkin Elmer). Alphalisa is a sandwichassay using biotinylated antibody attached to streptavidin coateddonorbeads and antibody conjugated to acceptor beads. In the presence ofantigen, the beads come into close proximity. The excitation of thedonor beads provokes the release of singlet oxygen molecules thattrigger a cascade of energy transfer in the acceptor beads, resulting inlight emission. To quantify the amount of Aβ42 in the cell supernatant,monoclonal antibody specific to the C-terminus of Aβ42 (JRF/cAβ42/26)was coupled to the receptor beads and biotinylated antibody specific tothe N-terminus of Aβ (JRF/AβN/25) was used to react with the donorbeads. To quantify the amount of Aβtotal in the cell supernatant,monoclonal antibody specific to the N-terminus of Aβ (JRF/AβN/25) wascoupled to the receptor beads and biotinylated antibody specific to themid region of Aβ (biotinylated 4G8) was used to react with the donorbeads.

To obtain the values reported in Table 3, the data are calculated aspercentage of the maximum amount of amyloid Beta 42 measured in theabsence of the test compound. The sigmoidal dose response curves wereanalyzed using non-linear regression analysis with percentage of thecontrol plotted against the log concentration of the compound. A4-parameter equation was used to determine the IC₅₀.

TABLE 3 IC50 IC50 Co. Aβ42 Aβtotal No. (μM) (μM) 1 0.06 >10 3 >10 >104 >10 >10 5 0.60 >15 6 3.31 >10 7 1.66 >10 8 5.50 >10 9 0.23 >15 382.46 >10 39 0.63 >10 10 0.53 >10 11 0.53 >10 12 0.59 >10 13 0.14 >10 140.17 >10 15 0.43 >10 16 1.55 >10 17 0.31 >10 18 1.12 >10 19 1.41 >10 200.10 >10 21 n.d. n.d. 22 0.76 >10 23 0.36 >10 24 0.13 >10 25 7.24 >10 260.12 >10 27 0.22 >10 28 0.33 >10 29 0.69 >10 30 0.07 >10 31 0.34 >10 320.35 >10 33 0.06 >10 34 0.14 >15 35 0.03 >10 36 0.06 >10 37 0.03 >10 410.38 >10 42 0.65 >10 43 2.14 >10 44 0.68 >10 45 n.d. n.d. 46 0.16 >10 470.10 >10 48 0.08 >10 49 0.07 >10 50 0.22 >10 51 6.02 >10 52 0.21 >10 400.03 >10 53 0.02 >10 54 0.09 >10 55 0.03 >10 56 0.06 >10 57 0.01 5.01 580.42 >10 59 0.10 >10 60 1.32 >10 61 0.05 10 62 0.02 >10 63 0.02 6.46 640.04 >10 65 0.02 3.47 66 0.37 >10 67 3.02 >10 68 0.1 >10 69 0.03 >10 700.93 >10 71 0.25 >10 72 0.05 >10 73 0.01 6.31 74 0.03 >10 75 0.03 >10 760.01 >10 77 0.18 >10 78 0.03 >10 79 0.009 1.95 80 0.27 8.13 81 0.5 >1082 0.02 7.76 83 0.01 4.37 84 0.01 3.89 85 0.01 7.24 86 0.007 2.19 870.25 8.91 88 0.04 >10 89 0.006 2.09 90 0.12 >10 91 0.02 4.68 92 0.22 >1093 0.04 >10 94 n.d. n.d. 95 0.24 >10 96 0.02 >10 97 0.007 6.7698 >10 >10 99 0.59 >10 100 0.34 >10 101 0.1 >10 102 0.12 >10 1030.12 >10 104 0.19 >10 (“n.d.” means not determined)

B) Demonstration of In Vivo Efficacy B-1) Aβ42

Aβ42 lowering agents of the invention can be used to treat AD in mammalssuch as humans or alternatively demonstrating efficacy in animal modelssuch as, but not limited to, the mouse, rat, or guinea pig. The mammalmay not be diagnosed with AD, or may not have a genetic predispositionfor AD, but may be transgenic such that it overproduces and eventuallydeposits Aβ in a manner similar to that seen in humans afflicted withAD.

Aβ42 lowering agents can be administered in any standard form using anystandard method. For example, but not limited to, Aβ42 lowering agentscan be in the form of liquid, tablets or capsules that are taken orallyor by injection. Aβ42 lowering agents can be administered at any dosethat is sufficient to significantly reduce levels of Aβ42 in the blood,blood plasma, serum, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of an Aβ42 lowering agentwould reduce Aβ42 levels in vivo, non-transgenic rodents, e.g. mice orrats were used. Animals treated with the Aβ42 lowering agent wereexamined and compared to those untreated or treated with vehicle andbrain levels of soluble Aβ42, Aβ40, Aβ38, and Aβ37 were quantitated byMeso Scale Discovery's (MSD) electrochemiluminescence detectiontechnology. Treatment periods varied from hours (h) to days and wereadjusted based on the results of the Aβ42 lowering once a time course ofonset of effect could be established.

A typical protocol for measuring Aβ42 lowering in vivo is shown but itis only one of many variations that could be used to optimize the levelsof detectable Aβ. For example, Aβ42 lowering compounds were formulatedin 20% of Captisol® (a sulfobutyl ether of β-cyclodextrin) in water or20% hydroxypropyl βcyclodextrin. The Aβ42 lowering agents wereadministered as a single oral dose or by any acceptable route ofadministration to overnight fasted animals. After 4 h, the animals weresacrificed and Aβ42 levels were analysed.

Blood was collected by decapitation and exsanguinations in EDTA-treatedcollection tubes. Blood was centrifuged at 1900 g for 10 minutes (min)at 4° C. and the plasma recovered and flash frozen for later analysis.The brain was removed from the cranium and hindbrain. The cerebellum wasremoved and the left and right hemisphere were separated. The lefthemisphere was stored at −18° C. for quantitative analysis of testcompound levels. The right hemisphere was rinsed with phosphate-bufferedsaline (PBS) buffer and immediately frozen on dry ice and stored at −80°C. until homogenization for biochemical assays.

Mouse brains from non-transgenic animals were resuspended in 8 volumesof 0.4% DEA (diethylamine)/50 mM NaCl containing protease inhibitors(Roche-11873580001 or 04693159001) per gram of tissue, e.g. for 0.158 gbrain, add 1.264 ml of 0.4% DEA. All samples were homogenized in theFastPrep-24 system (MP Biomedicals) using lysing matrix D (MPBio#6913-100) at 6 m/s for 20 seconds. Homogenates were centrifuged at20800×g for 5 min and supernatants collected. Supernatants werecentrifuged at 221.300×g for 50 min. The resulting high speedsupernatants were then transferred to fresh eppendorf tubes. Nine partsof supernatant were neutralized with 1 part 0.5 M Tris-HCl pH 6.8 andused to quantify Aβ.

To quantify the amount of Aβ42, Aβ40, Aβ38, and Aβ37 in the solublefraction of the brain homogenates, simultaneous specific detection ofAβ42, Aβ40, Aβ38, and Aβ37 was performed using MSD'selectro-chemiluminescence multiplex detection technology. In this assaypurified monoclonal antibodies specific for Abeta37 (JRD/Aβ37/3),Abeta38 (J&JPRD/Aβ38/5), Abeta40 (JRF/cAβ40/28), and Abeta42(JRF/cAβ42/26) were coated on MSD 4-plex plates. Briefly, the standards(a dilution of synthetic Aβ42, Aβ40, Aβ38, and A(337) were prepared in1.5 ml Eppendorf tube in Ultraculture, with final concentrations rangingfrom 10000 to 0.3 pg/m. The samples and standards were co-incubated withSulfo-tag labelled JRF/rAβ/2 antibody to the N-terminus of Aβ asdetector antibody. 50 μl of conjugate/sample or conjugate/standardsmixtures were then added to the antibody-coated plate. The plate wasallowed to incubate overnight at 4° C. in order to allow formation ofthe antibody-amyloid complex. Following this incubation and subsequentwash steps the assay was finished by adding read buffer according to themanufacturer's instructions (Meso Scale Discovery, Gaitherburg, Md.).

The SULFO-TAG emits light upon electrochemical stimulation initiated atthe electrode. MSD Sector instrument SI6000 was used for signalread-out.

In this model a Aβ42 lowering compared to untreated animals would beadvantageous, in particular a Aβ42 lowering with at least 10%, more inparticular a Aβ42 lowering with at least 20%.

B-2) Aβ38

Aβ38 increasing agents of the invention can be used to treat AD inmammals such as humans or alternatively demonstrating efficacy in animalmodels such as, but not limited to, the mouse, rat, or guinea pig. Themammal may not be diagnosed with AD, or may not have a geneticpredisposition for AD, but may be transgenic such that it overproducesand eventually deposits Aβ in a manner similar to that seen in humansafflicted with AD.

Aβ38 increasing agents can be administered in any standard form usingany standard method. For example, but not limited to, Aβ38 increasingagents can be in the form of liquid, tablets or capsules that are takenorally or by injection. Aβ38 increasing agents can be administered atany dose that is sufficient to significantly increase levels of Aβ38 inthe blood, plasma, serum, cerebrospinal fluid (CSF), or brain.

To determine whether acute administration of an Aβ38 increasing agentswould increase Aβ38 levels in vivo, non-transgenic rodents, e.g. mice orrats were used. Animals treated with the Aβ38 increasing agents wereexamined and compared to those untreated or treated with vehicle andbrain levels of soluble Aβ42, Aβ40, Aβ38, and Aβ37 were quantitated byMSD electrochemiluminescence detection technology. Treatment periodsvaried from hours (h) to days and were adjusted based on the results ofthe Aβ38 increase once a time course of onset of effect could beestablished.

A typical protocol for measuring Aβ38 increase in vivo is shown but itis only one of many variations that could be used to optimize the levelsof detectable Aβ. For example, Aβ38 increasing agents were formulated in20% of Captisol® (a sulfobutyl ether of β-cyclodextrin) in water or 20%hydroxypropyl βcyclodextrin. The Aβ38 increasing agents wereadministered as a single oral dose or by any acceptable route ofadministration to overnight fasted animals. After 4 h, the animals weresacrificed and Aβ38 levels were analysed.

Blood was collected by decapitation and exsanguinations in EDTA-treatedcollection tubes. Blood was centrifuged at 1900 g for 10 minutes (min)at 4° C. and the plasma recovered and flash frozen for later analysis.The brain was removed from the cranium and hindbrain. The cerebellum wasremoved and the left and right hemisphere were separated. The lefthemisphere was stored at −18° C. for quantitative analysis of testcompound levels. The right hemisphere was rinsed with phosphate-bufferedsaline (PBS) buffer and immediately frozen on dry ice and stored at −80°C. until homogenization for biochemical assays.

Mouse brains from non-transgenic animals were resuspended in 8 volumesof 0.4% DEA (diethylamine)/50 mM NaCl containing protease inhibitors(Roche-11873580001 or 04693159001) per gram of tissue, e.g. for 0.158 gbrain, add 1.264 ml of 0.4% DEA. All samples were homogenized in theFastPrep-24 system (MP Biomedicals) using lysing matrix D (MPBio#6913-100) at 6 m/s for 20 seconds. Homogenates were centrifuged at20800×g for 5 min and supernatants collected. Supernatants werecentrifuged at 221.300×g for 50 min. The resulting high speedsupernatants were then transferred to fresh eppendorf tubes. Nine partsof supernatant were neutralized with 1 part 0.5 M Tris-HCl pH 6.8 andused to quantify Aβ.

To quantify the amount of Aβ42, Aβ40, Aβ38, and Aβ37 in the solublefraction of the brain homogenates, simultaneous specific detection ofAβ42, Aβ40, Aβ38, and Aβ37 was performed using MSD'selectro-chemiluminescence multiplex detection technology. In this assaypurified monoclonal antibodies specific for Abeta37 (JRD/Aβ37/3),Abeta38 (J&JPRD/Aβ38/5), Abeta40 (JRF/cAβ40/28), and Abeta42(JRF/cAβ42/26) were coated on MSD 4-plex plates. Briefly, the standards(a dilution of synthetic Aβ42, Aβ40, Aβ38, and Aβ37) were prepared in1.5 ml Eppendorf tube in Ultraculture, with final concentrations rangingfrom 10000 to 0.3 pg/m. The samples and standards were co-incubated withSulfo-tag labelled JRF/rAβ/2 antibody to the N-terminus of Aβ asdetector antibody. 50 μl of conjugate/sample or conjugate/standardsmixtures were then added to the antibody-coated plate. The plate wasallowed to incubate overnight at 4° C. in order to allow formation ofthe antibody-amyloid complex. Following this incubation and subsequentwash steps the assay was finished by adding read buffer according to themanufacturer's instructions (Meso Scale Discovery, Gaitherburg, Md.).

The SULFO-TAG emits light upon electrochemical stimulation initiated atthe electrode. MSD Sector instrument SI6000 was used for signalread-out.

In this model a Aβ38 increase compared to untreated animals would beadvantageous, in particular a Aβ38 increase with at least 10%, more inparticular a Aβ38 increase with at least 20%.

B-3) Results

The results are shown in Table 4 (dose 30 mg/kg oral dosing) (value foruntreated animals as control (Ctrl) was set at 100):

Aβ40 Aβ42 Aβ38 Co. No. (% vs Ctrl)_Mean (% vs Ctrl)_Mean (% vsCtrl)_Mean 13 101 77 117 30 126 118 121 33  79 57 132 34 128 104 102 35108 112 116 48  91 60 161 49 101 85 123 53 121 120 124 55 113 93 142 57 105* 100 134 61  90 86 192 62  87 82 113 63  62* 58 135 64  132* 108155 65  52 58 165 72  88* 64 130 73  114* 97 110 74  100# 83 144 79  62*54 175 83  41* 40 166 84  21* 25 237 85  69* 51 194 89  67# 58 132 *30mpk sc; #10 mpk po

Composition Examples

“Active ingredient” (a.i.) as used throughout these examples relates toa compound of Formula (I), including any tautomer or stereoisomeric formthereof, or a pharmaceutically acceptable addition salt or a solvatethereof; in particular to any one of the exemplified compounds.

Typical examples of recipes for the formulation of the invention are asfollows:

1. Tablets

Active ingredient 5 to 50 mg Di-calcium phosphate 20 mg Lactose 30 mgTalcum 10 mg Magnesium stearate 5 mg Potato starch ad 200 mg

2. Suspension

An aqueous suspension is prepared for oral administration so that eachmilliliter contains 1 to 5 mg of active ingredient, 50 mg of sodiumcarboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg of sorbitol andwater ad 1 ml,

3. Injectable

A parenteral composition is prepared by stirring 1.5% (weight/volume) ofactive ingredient in 0.9% NaCl solution or in 10% by volume propyleneglycol in water.

4. Ointment

Active ingredient 5 to 1000 mg Stearyl alcohol 3 g Lanoline 5 g Whitepetroleum 15 g Water ad 100 g

In this Example, active ingredient can be replaced with the same amountof any of the compounds according to the present invention, inparticular by the same amount of any of the exemplified compounds.

1. A compound of Formula (I)

a tautomer or a stereoisomeric form thereof, wherein R¹ is Ar¹ or Ar²;R² is hydrogen, phenyl, cycloC₃₋₇alkyl, 3,4,5,6-tetrahydropyranyl,3,4,5,6-tetrahydrothiopyranyl, piperidinyl, or C₁₋₄alkyl optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halo, hydroxyl, C₁₋₄alkyloxy and NR⁷R⁸; Zis methylene or 1,2-ethanediyl, wherein methylene or 1,2-ethanediyl isoptionally substituted with one or two C₁₋₄alkyl substituents; L is acovalent bond, 1,2-cyclopropanediyl, —C(═O)—C₁₋₆alkanediyl-,C₁₋₆alkanediyl optionally substituted with one or more substituentsselected from the group consisting of 3,4,5,6-tetrahydropyranyl, phenyland C₁₋₄alkyloxy-C₁₋₄alkyl, or C₁₋₆alkanediyl wherein two geminalhydrogen atoms are replaced by C₂₋₆alkanediyl; Ar¹ is a ring systemselected from the group consisting of imidazolyl, 1,2,4-triazolyl,1,3,4-triazolyl, pyrrolyl, furanyl, isoxazolyl, isothiazolyl, thienyl,thiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl,4,5,6,7-tetrahydro-benzo[b]thienyl, 1,2-benzisoxazolyl, benzofuranyl,2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and1,2,3,4-tetrahydroquinolinyl; wherein said ring system is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halo, oxo, Ar^(a), R⁰, C₁₋₄alkyl optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₁₋₄alkyloxy and cycloC₃₋₇alkyl, andC₁₋₄alkyloxy optionally substituted with one or more substituents eachindependently selected from the group consisting of halo and cycloC₃₋₇alkyl; Ar² is phenyl substituted with one substituent selected from thegroup consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said phenylis optionally substituted with one, two or three substituents eachindependently selected from the group consisting of halo, C₁₋₄alkyloxyoptionally substituted with one or more halo substituents, and C₁₋₄alkyloptionally substituted with one or more halo substituents; Ar³ is phenyloptionally substituted with one or more substituents each independentlyselected from the group consisting of halo and C₁₋₄alkyl optionallysubstituted with one or more halo substituents; R³ is hydrogen, cyano,halo, C₁₋₄alkyloxy or C₁₋₄alkyl; R⁴ is hydrogen, halo or C₁₋₄alkyl; R⁵is hydrogen or C₁₋₄alkyl; X is CR⁶ or N; R⁶ is hydrogen or C₁₋₄alkyl; R⁷is hydrogen or C₁₋₄alkyl; R⁸ is hydrogen or C₁₋₄alkyl; R⁹ is hydrogen,cycloC₃₋₇alkyl or phenyl; R⁰ is a ring system selected from the groupconsisting of piperidinyl, morpholinyl, cycloC₃₋₇alkyl, pyrazolyl andpyrrolidinyl; wherein said ring system is optionally substituted withone or more substituents each independently selected from the groupconsisting of halo or C₁₋₄alkyl optionally substituted with one or morehalo atoms; or a pharmaceutically acceptable addition salt.
 2. Thecompound according to claim 1, wherein R¹ is Ar¹ or Ar²; R² is hydrogenor C₁₋₄alkyl; Z is methylene or 1,2-ethanediyl, wherein methylene or1,2-ethanediyl is optionally substituted with one or two C₁₋₄alkylsubstituents; L is a covalent bond, 1,2-cyclopropanediyl,—C(═O)—C₁₋₆alkanediyl-, C₁₋₆alkanediyl or C₁₋₆alkanediyl wherein twogeminal hydrogen atoms are replaced by C₂₋₆alkanediyl; Ar¹ is a ringsystem selected from the group consisting of imidazolyl,1,2,4-triazolyl, 1,3,4-triazolyl, pyrrolyl, furanyl, isoxazolyl,isothiazolyl, thienyl, thiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl,4,5,6,7-tetrahydro-benzo[b]thienyl, 1,2-benzisoxazolyl, benzofuranyl,2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,1,2,3,4-tetrahydro-isoquinolinyl, 2,3-dihydro-benzo[b]thienyl,1,3-dihydro-benzo[c]thienyl, 2-benzofuranyl,3,4-dihydro-2-benzothiopyranyl, 3,4-dihydro-2-benzopyranyl and1,2,3,4-tetrahydroquinolinyl; wherein said ring system is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halo, oxo, R⁰, C₁₋₄alkyl optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halo, C₁₋₄alkyloxy and cycloC₃₋₇alkyl, andC₁₋₄alkyloxy optionally substituted with one or more substituents eachindependently selected from the group consisting of halo andcycloC₃₋₇alkyl; Ar² is phenyl substituted with one substituent selectedfrom the group consisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; andsaid phenyl is optionally substituted with one, two or threesubstituents each independently selected from the group consisting ofhalo, C₁₋₄alkyloxy optionally substituted with one or more halosubstituents, and C₁₋₄alkyl optionally substituted with one or more halosubstituents; R³ is hydrogen; R⁴ is C₁₋₄alkyl; R⁵ is hydrogen; X is CR⁶;R⁶ is hydrogen; R⁹ is hydrogen, cycloC₃₋₇alkyl or phenyl; R⁰ ispiperidinyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halo or C₁₋₄alkyloptionally substituted with one or more halo atoms.
 3. The compoundaccording to claim 2, wherein R¹ is Ar¹ or Ar²; R² is hydrogen orC₁₋₄alkyl; Z is methylene; L is a covalent bond, —C(═O)—C₁₋₆alkanediyl-,C₁₋₆alkanediyl, or C₁₋₆alkanediyl wherein two geminal hydrogen atoms arereplaced by C₂₋₆alkanediyl; Ar¹ is a ring system selected from the groupconsisting of thienyl, thiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl,4,5,6,7-tetrahydro-benzo[b]thienyl, 1,2-benzisoxazolyl, benzofuranyl,2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl,1,2,3,4-tetrahydro-isoquinolinyl; wherein said ring system is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halo, Ar^(a), oxo, R⁰, C₁₋₄alkyl optionallysubstituted with one or more halo substituents, and C₁₋₄ alkyloxy; Ar²is phenyl substituted with one substituent selected from the groupconsisting of OR⁹ and 3-azabicyclo[3.1.0]hexanyl; and said phenyl isoptionally substituted with one, two or three substituents eachindependently selected from the group consisting of C₁₋₄alkyloxyoptionally substituted with one or more halo substituents, and C₁₋₄alkyloptionally substituted with one or more halo substituents; Ar³ is phenyloptionally substituted with one or more CF₃ substituents; R³ ishydrogen; R⁴ is C₁₋₄alkyl; R⁵ is hydrogen; X is CR⁶; R⁶ is hydrogen; R⁹is hydrogen, cycloC₃₋₇alkyl or phenyl; R⁰ is a ring system selected fromthe group consisting of piperidinyl optionally substituted with one ormore C₁₋₄alkyl groups optionally substituted with one or more haloatoms.
 4. The compound according to claim 3, wherein R¹ is Ar¹, whereinAr¹ is a ring system selected from the group consisting of imidazolyl,thienyl, thiazolyl, pyrrolidinyl, piperidinyl,4,5,6,7-tetrahydro-benzo[b]thienyl, benzofuranyl,2,3-dihydrobenzofuranyl, 1,3-dihydro-isobenzofuranyl,5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo-[1,5-a]pyridinyl,3,4-dihydro-1-benzopyranyl, indazolyl, 1,2,3,4-tetrahydro-isoquinolinyl.5. The compound according to claim 3, wherein R¹ is Ar².
 6. The compoundaccording to claim 5, wherein R² is C₁₋₄alkyl.
 7. The compound accordingto claim 6, wherein Z is methylene.
 8. The compound according to claim7, wherein R² is C₁₋₄alkyl and L is C₁₋₆alkanediyl.
 9. The compoundaccording to claim 8, wherein X is CR⁶.
 10. The compound according toclaim 9, wherein the carbon atom substituted with R² has the Rconfiguration.
 11. The compound according to claim 10 wherein theposition of R³ is fixed as shown in formula (I-x)


12. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and, as active ingredient, a therapeuticallyeffective amount of a compound according to claim
 1. 13.-15. (canceled)16. A method of treating a disease or condition selected fromAlzheimer's disease, traumatic brain injury, mild cognitive impairment,senility, dementia, dementia with Lewy bodies, cerebral amyloidangiopathy, multi-infarct dementia, dementia pugilistica, Down'ssyndrome, dementia associated with Parkinson's disease and dementiaassociated with beta-amyloid, comprising administering to a subject inneed thereof, a therapeutically effective amount of a compound accordingto claim
 1. 17. The method according to claim 16, wherein the disease isAlzheimer's disease.
 18. A method of treating or preventing a disease orcondition selected from neurocognitive disorder due to Alzheimer'sdisease, neurocognitive disorder due to traumatic brain injury,neurocognitive disorder due to Lewy body disease, neurocognitivedisorder due to Parkinson's disease or vascular neurocognitive disorder,comprising administering to a subject in need thereof, a therapeuticallyeffective amount of a pharmaceutical composition according to claim 12.19. (canceled)